US Pharm. 2018:43(2)(Specialty&Oncology suppl):2-5.

ABSTRACT: Chemotherapy-induced nausea and vomiting (CINV) is one of the most common side effects of chemotherapy treatment. Poorly managed CINV is associated with a high economic burden and decreased quality of life. While the mechanism underlying CINV is complex and remains to be fully elucidated, there have been numerous neurotransmitters implicated in the mediation of CINV. Various guidelines have been developed to assist practitioners with the prevention and treatment of CINV. The treatment recommendations are tailored to the emetogenicity of the chemotherapeutic agent(s), with prevention of CINV being critical to successful management of CINV. The therapeutic drug classes utilized in the prevention and/or treatment of CINV include 5-HT₃ antagonists, NK-1 antagonists, corticosteroids, and dopamine antagonists. The atypical antipsychotic olanzapine has demonstrated effectiveness in the management of CINV, antagonizing multiple receptors in CINV. Oral cannabinoids such as dronabinol have been used in patients who fail to respond to conventional CINV treatment. More studies are needed to determine the effects and role of cannabis in CINV.

An estimated 80% of patients with cancer will experience chemotherapy-induced nausea and vomiting (CINV).¹ The term CINV includes emesis and nausea, which can involve a loss of appetite and result in decreased oral intake of fluids and calories.¹ Prevention is the primary goal in the management of CINV. Poorly managed nausea and vomiting decrease the patient’s quality of life and may lead to disruptions in cancer treatments. Serious complications from CINV include dehydration, malnutrition, electrolyte imbalances, esophageal tears, fractures, wound dehiscence, and deterioration of physical and mental status.¹ As medical costs and the incidence of cancer continue to increase, the management of CINV becomes more important in order to reduce the economic burden to patients and the healthcare system. There are various guidelines published to help practitioners appropriately manage CINV. The severity, type, and duration of CINV differs based on patient (Table 1) and drug-specific risk factors (Table 2).^1,2 Table 2 provides selected examples of the emetogenicity of drugs, drug doses, and regimens.

PATHOPHYSIOLOGY

Two primary mechanisms have been suggested in the pathophysiology of the emetic response. One is through a central pathway that includes the chemoreceptor trigger zone, an area located outside of the blood-brain barrier in the medulla oblongata. The other is through a peripheral pathway involving the vagal afferent nerves in the gastrointestinal tract. Various neurotransmitter receptors including dopamine, 5-hydroxytryptamine type 3 (5-HT₃, serotonin), neurokinin-1 (NK-1), and cholecystokinin are activated by chemotherapy, causing an emetic response.³ The multiple pathways are thought to be responsible for the different types of CINV: acute emesis is mediated by the stimulation of the peripheral pathway, while delayed emesis comes from the stimulation of the central pathway.^3,4

Five different types of CINV have been defined and include acute, delayed, breakthrough, anticipatory, and refractory CINV.^1,3-5 Acute CINV occurs within the first 24 hours after treatment, with a peak around hours 5 to 6.^3,4 Delayed CINV manifests between 1 and 5 days after chemotherapy administration and commonly results from the use of cisplatin, carboplatin, and cyclophosphamide. Breakthrough CINV occurs when patients experience nausea or vomiting despite the use of recommended preventive antiemetics. Anticipatory CINV occurs before treatment and develops as a conditioned response when a patient has experienced CINV from a previous treatment. The conditioning can include any neutral stimulus (i.e., smells, colors) associated with treatment and occurs in up to 45% of patients, with nausea more common than vomiting.^1,4,5 Refractory CINV occurs after chemotherapy despite the appropriate use of antiemetic prophylactic and rescue treatments.^3-5

GUIDELINES FOR TREATMENT

Numerous organizations have published guidelines for the management of CINV. Commonly accepted and widely used among clinicians are the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Multinational Association of Supportive Care in Cancer (MASCC) guidelines. These recommendations concur that the key for the prevention of acute and delayed CINV is prophylaxis therapy. See Table 3 for a list of medications and their indications.

PHARMACOLOGIC THERAPY

5-HT₃ Antagonists

Serotonin is the primary neurotransmitter implicated in acute CINV. The 5-HT₃ receptor antagonists block serotonin receptors in the chemoreceptor trigger zone and the gastrointestinal tract. There are four medications classified as 5-HT₃ antagonists on the market (dolasetron, granisetron, ondansetron, and palonosetron). As a class, the 5-HT₃ antagonists are commercially available in several formulations, including oral (tablets, disintegrating tablets, solution, and dissolving film), IV (premixed solutions, vials, and extended-release solution), and a transdermal patch. This multiplicity of dosage forms offers many options to improve delivery and adherence. Common side effects of 5-HT₃ antagonists include fatigue, malaise, and gastrointestinal disturbances (e.g., constipation, diarrhea, abdominal pain).⁶ QT prolongation is a serious adverse effect with 5-HT₃ antagonists.^6,7 For this reason, dolasetron IV is no longer commercially available, and the maximum IV dose of ondansetron is limited to 16 mg. Caution should be used in patients at high risk for cardiac abnormalities. Monitoring may include serum electrolytes and ECGs.^6,7 Clinicians should be aware of the significant drug-drug interactions and possible serotonin syndrome that may arise when 5-HT₃ receptor antagonists are coadministered with other serotonin agents, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants.^8,9 Serotonin syndrome is a potentially life-threatening condition that may develop when patients have elevated serotonin levels, causing autonomic dysfunction, neuromuscular excitation, and altered mental status.⁸ Palonosetron is often recommended by the guidelines due to the drug’s higher binding affinity to 5-HT₃ receptors and longer half-life compared with others in this class.⁶ Palonosetron is also the only 5-HT₃ antagonist available in a combination product with an NK-1 antagonist, netupitant.

NK-1 Antagonists

Substance P is another neurotransmitter involved in the mediation of CINV. The NK-1 receptor antagonists block substance P from binding to its neurokinin receptors and play a pivotal role in the prevention of delayed CINV.⁹ There are three drugs in this class (aprepitant, fosaprepitant, and rolapitant). Aprepitant is an oral NK-1 receptor antagonist that crosses the blood-brain barrier and is given once daily for 3 to 4 days. Fosaprepitant, a prodrug of aprepitant, is given as a one-time IV dose. Aprepitant inhibits CYP3A4 and induces CYP2C9 metabolic pathways. This can lead to many significant drug-drug interactions (e.g., oral contraceptives, warfarin, and dexamethasone).¹⁰ Rolapitant is the only medication in this class that is not an inhibitor of CYP3A4, which can be advantageous in avoiding some drug-drug interactions. Unlike other NK-1 antagonists, rolapitant does not need a dose reduction when combined with dexamethasone or other CYP3A4-metabolized medications.^3,11-13 Common adverse effects include diarrhea, fatigue, and neutropenia.⁶

Other Agents

Olanzapine: Olanzapine is an FDA-approved antipsychotic medication that blocks dopamine, serotonin, and histamine receptors.² There is a growing body of literature to support the use of olanzapine for the prevention and treatment of CINV; olanzapine is also discussed within the clinical practice guidelines.^11-13 Olanzapine may be used in combination with palonosetron and dexamethasone for the prevention of CINV in moderate- and high-emetogenic chemotherapies.^12,13 Olanzapine has demonstrated a significant reduction in acute (P <.0001) and delayed (P <.004) nausea at a dose of 5 mg twice daily.¹⁴ These outcomes add to the increasing number of studies supporting the role of olanzapine for CINV. Olanzapine may increase the risk of QT prolongation when used in combination with other QT-prolongation agents. It should also be used with caution with metoclopramide or phenothiazine antiemetics due to the increase risk of extrapyramidal side effects and excessive sedation. Clinicians should counsel patients regarding the risk of CNS depression, orthostatic hypotension, and an increased risk for falls.¹² 

Dexamethasone: Dexamethasone is commonly used in the prevention and treatment of CINV. It works synergistically to increase the effectiveness of other CINV agents, although the exact mechanism remains to be elucidated.⁵ Since dexamethasone is a corticosteroid, patients should be counseled about potential adverse effects of steroids including insomnia, hyperglycemia, indigestion, agitation, increased appetite, and weight gain.²

Dopamine Antagonists: Dopamine antagonists such as metoclopramide, promethazine, and prochlorperazine (phenothiazines) are still commonly used in practice for breakthrough CINV. Metoclopramide is used less frequently due to the increased risk for irreversible extrapyramidal side effects, including akathisia (feelings of inner restlessness), dystonia (involuntary muscle contractions), tardive dyskinesia (movement disorder), and drug-induced parkinsonism (tremor, bradykinesia, cogwheeling).¹⁵ This risk is higher in patients aged less than 30 years and may be reduced by pretreating with diphenhydramine.⁶ Intravenous promethazine is a known irritant and has an extravasation warning from the Institute for Safe Medication Practices. Promethazine IV must be diluted prior to administration.¹⁶

Cannabinoids: The FDA-approved synthetic cannabinoids (i.e., dronabinol and nabilone) have been used in the treatment of CINV since the 1980s, particularly in those patients who experience refractory CINV despite conventional antiemetics.^11-13 Owing to recent increases in the accessibility of cannabis, research is now more focused on the medical use of marijuana.^1,17 There may be growing support for the use of cannabis for CINV. However, its use is limited by its Schedule I status and the complex compositions of pharmacologically active components. Due to the variability of the concentration of active components, researchers are having a difficult time creating protocols and establishing adequate control groups.^1,17,18 cannabis is available to patients in 28 states, with this number increasing steadily.¹⁷ The future of cannabis use in CINV is uncertain, and more clinical studies and evidence are needed to justify its mainstream use.

Recommendations for Multidrug Antiemetic Therapy

Best practice recommendations consist of a prophylactic regimen utilizing multiple drugs that target the various neurotransmitters involved in acute and delayed CINV. A triple-drug approach is often employed for moderate- to high-emetogenic chemotherapy and includes a 5-HT₃ antagonist, NK-1 antagonist, and dexamethasone. Olanzapine in combination with other antiemetics was recently added to the ASCO and NCCN guidelines. The prevention regimen for moderately emetogenic chemotherapy often consists of dual therapy with dexamethasone plus a 5-HT₃ antagonist and may include the addition of an NK-1 antagonist if the patient has additional risk factors. Most single-agent antiemetics may be used as prophylactic therapy for CINV with a low emetic risk.^11-13 See the NCCN, ASCO, and MASCC guidelines for selected regimens for high-emetic risk IV chemotherapy. For breakthrough nausea and vomiting, the guidelines agree that an agent from a different therapeutic class can be added to the current prophylactic regimen. The rationale is that the previously selected therapies were ineffective in preventing CINV.^11-13 Anticipatory nausea and vomiting may be prevented by using behavioral therapy, with the possible addition of a benzodiazepine.^11-13

Nonpharmacologic Therapy

There are many nonpharmacologic treatment options for CINV. While pharmacologic therapy continues to be the mainstay for prophylaxis and treatment of CINV, nopharmacologic therapies provide adjunctive support. Clinical studies have demonstrated positive results with the use of acupuncture and acupressure.¹⁹ Ginger has been shown to be clinically effective for CINV, although it has not been well established as to what type of CINV is best treated with it. Other nonpharmacologic options include dietary alterations (bland diet, small meals), relaxation techniques, hypnosis, guided imagery, and behavioral therapy.¹

PHARMACIST’S ROLE

Pharmacists play an important and active role in helping patients prevent and treat one of the most debilitating side effects of chemotherapy treatments. A key role for pharmacists in CINV is to ensure patient therapies are consistent with guideline recommendations. One study demonstrated the need for guideline adherence. This is because significantly more cancer patients receiving antiemetic therapy recommended in the guidelines experienced no CINV for 5 days compared with patients receiving therapy inconsistent with guidelines (53.4% vs. 43.8% respectively; P <.001).¹⁸ Patients experiencing breakthrough CINV should be switched to a different therapeutic class to treat their CINV.^11-13 If patients are struggling with the cost burden of CINV, it may be helpful to consider a less-expensive alternative agent within the same therapeutic class or consider combination products.³ Pharmacists should educate patients about CINV and the various nonpharmacologic and pharmacologic treatment options available. Patients should be counseled on the use of each medication and the reasons for strict adherence in order to avoid severe complications.

CONCLUSION

CINV is a common side effect for patients who are receiving chemotherapy. It can be prevented and treated through pharmacologic and nonpharmacologic therapy options. Multimodal treatment strategies should be considered on a patient-by-patient basis in conformance with published treatment guidelines. Pharmacists can play a key role in managing these side effects and helping patients maintain their quality of life during this difficult time.

REFERENCES

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