Approximately 70% to 80% of all patients who receive chemotherapy experience nausea and vomiting, which can disrupt their lives in numerous ways. Chemotherapy-induced nausea and vomiting (CINV) has traditionally been classified according to three patterns: acute, delayed, and anticipatory. Additional classifications include refractory and breakthrough nausea and vomiting. The mechanisms by which chemotherapy causes nausea and vomiting are complex, but the most common is thought to be activation of the chemoreceptor trigger zone. An appreciation of the risk factors for developing CINV is important when matching antiemetic treatment to risk. The emetogenicity of the chemotherapy regimen-generally categorized as high, moderate, low, or minimal- greatly affects a patient's risk for developing CINV. In addition to established and emerging pharmacologic approaches to managing CINV, many complementary and integrated modalities may be options. Progress in CINV management must include a better understanding of its etiology and a focus on prevention. This review will consider the etiology, assessment, and treatment of patients with CINV.
Patient Risk Factors
An appreciation of the risk factors for developing CINV is important when matching antiemetic treatment to risk. Prognostic indicators for developing chemotherapy-induced nausea and vomiting include those that are intrinsic to the patient, the chemotherapy, or the tumor. Patient characteristics that may affect antiemetic control include prior experience with chemotherapy, alcohol intake history, age, and gender. A previous experience with chemotherapy often sets the stage for success or failure in controlling emesis during future courses of chemotherapy. Giving the appropriate antiemetic medication as part of the plan during the initial course of chemotherapy often eliminates the subsequent chance of anticipatory CINV (and may decrease the severity of delayed emesis). Other patient-specific risk factors exist. Chronic and heavy alcohol intake (ie, > 100 g of ethanol or five mixed drinks per day), whether past or current, has been shown to positively affect the control of emesis. In contrast, someone who is sensitive to the effects of drinking alcohol (eg, feeling warm, drowsy, or nauseous) with relatively light or rare intake might have a higher chance of experiencing CINV. As a prognostic indicator, age cannot predict patient response to chemotherapy, but the tendency is that the younger the patient, the sicker he or she will become. Gender is another patient factor in considering risk for CINV. For unknown reasons, women achieve poorer control of emesis during treatment for various malignancies. A possible explanation might be that women tend to more often receive chemotherapy regimens with highly emetogenic agents such as cisplatin and cyclophosphamide, usually given together. Women are also less likely than men to have a history of high alcohol intake. Other contributing factors that may affect the control of emesis include fatigue, low social functioning, personal history of motion sickness, hyperemesis with pregnancy, anxiety, and prechemotherapy nausea [1,7].
Emetogenicity of Drugs
Certainly the emetogenicity of the regimen used greatly affects a patient's risk for developing chemotherapy- related nausea and vomiting. At least four different categories of emetogenic potential exist-high, moderate, low, and minimal-depending on the classification system one references (as there is no universal consensus on one classification system for the emetogenicity of cancer chemotherapy). That said, the emetogenicity of different agents is clearly diverse, which is one of the most important tools we have in the prevention and treatment of CINV (Table 3).
Of note is cisplatin, the prototype chemotherapy for emetogenicity risk level 5 (meaning the drug is associated with more than a 90% chance of emesis in the absence of effective an-tiemetic prophylaxis). More importantly, cisplatin is the cornerstone of therapy for many cancers, yet poses a universal risk (> 99%) of emesis at doses less than or equal to 50 mg/m2. It has a well characterized emetogenic profile that serves as a model for antiemetic testing. Thus, if an antiemetic is efficacious against the CINV of cisplatin, this can be predictive of antiemetic efficacy with other chemotherapeutic drugs.
The goals of therapy in the management of CINV are to enhance the patient's quality of life, eliminate nausea and vomiting, provide convenient care, reduce hospital and clinic time, and reduce treatment costs. The principal strategy for management of CINV is prevention. This concept of prevention is similar to that in pain management and more effective than salvage therapy. A goal of prevention reduces morbidity and medical complications and is cost-effective. Consequently, patients are more likely to complete treatment. It is important to be aware of the current antiemetic agents and thoughts for guiding their use to prevent and treat CINV. There is a growing diversity of antiemetic classes. As more is known about the causes and modulators of CINV, one can anticipate the antiemetic guidelines to evolve as well. As discussed previously, the five known neurotransmitter receptor sites of primary importance in the vomiting relex are M1 (muscarinic), D2 (dopamine), H1 (histamine), (5-hydroxytryptamine (5-HT)-3 (serotonin), and neurokinin 1 (NK) receptor (substance P). Consequently, the current antiemetic drug classes are anticholinergics (primarily for motion sickness prophylaxis), dopamine-receptor antagonists (phenothiazines, butyrophenones, and benzamides), antihistamines (primarily for motion sickness), serotonin-receptor antagonists, and the relatively new neurokinin-1-receptor antagonists. Three other general antiemetic classes with less well understood mechanisms of action are the corticosteroids, cannabinoids, and benzodiazepines.
Most Active Antiemetics
The antiemetic agents considered to be most active for the management of CINV are the type 3 serotonin (5-HT3)-receptor antagonists, corticosteroids, and metoclopramide, which has substantial antagonism at both serotonin- and dopamine-receptor sites. Of note is palonosetron, a second-generation 5-HT3 antagonist that is currently the only Food and Drug Administration (FDA)-approved serotonin antagonist for the prevention of delayed CINV with moderately emetogenic chemotherapy.
• Serotonin Antagonists—The antiemetic activity of metoclopramide is thought to be a serotonin antagonist, although substantial dopaminergic antagonist action exists as well. This explains the potential for extrapyramidal reactions. One must recognize the potential that exists for acute dystonic reactions in the setting of dopamine-receptor blocking agents such as phenothiazines (prochlorperazine, chlorpromazine, thiethylperazine [Torecan]), butyrophenones (droperidol, haloperidol), and substituted benzamides (metoclopramide). This alarming side effect is usually characterized by trismus or tortocollis. Within the patient population under age 30, chemotherapy that might call for antiemetic prophylaxis is often given over several consecutive days, thus increasing the possibility of acute dystonic reactions. The fact that 5-HT3 antiemetic agents do not cause acute dystonic reactions makes them an especially helpful treatment option for children and younger adults. In light of the possible side effects of metoclopramide, other treatment options were developed with a specific focus on blocking the serotonin receptor. Several selective 5-HT3 antagonists, including dolasetron (Anzemet), granisetron (Kytril), ondansetron (Zofran), tropistron, and palonosetron, are available internationally. Multiple large, randomized clinical trials have shown no clinically significant difference among these drugs when used appropriately, with the exception of palonosetron, which demonstrates a higher binding affinity at the receptor site.[8,9,23,24] Further studies have demonstrated that a single dose of a 5-HT3-receptor anatagonist prior to chemotherapy has efficacy equivalent to a multiple-dosing regimen.[25-27] Optimal dosing for the serotonin antagonists is controversial, as it appears that higher doses are not advantageous. For example, the majority of ondansetron trials have indicated that an 8-mg dose is as effective as the higher, more expensive dose of 32 mg.[29,30] In general, the side-effect profiles of 5-HT3 antagonists show an advantage over that of metoclopramide. Central nervous system effects, extrapyramidal reactions, and sedation are not observed with serotonin antagonists; this is particularly beneficial in younger patients. Common side effects of 5-HT3 antagonists include mild headache, transient transaminase elevations, and mild constipation with some agents.
• Corticosteroids—Corticosteroids constitute another of the more active antiemetic choices. The most studied example is dexamethasone in oral and parenteral form. This is an expensive agent, and the best dose has not been established, but a single dose of 10 to 20 mg appears to be adequate. Caution is warranted in the clinical setting of diabetes, steroid myopathy, or other instances where steroid intolerance may exist. However, the short recommended course makes a corticosteroid a safe and easy option to offer patients with CINV. For prevention of delayed emesis, adequate doses of corticosteroids are viewed as advantageous when combined with metoclopramide . The addition of a corticosteroid to 5-HT3 antagonists greatly improves antiemetic efficacy with each agent. This effect is seen with cisplatin as well as with anthracyclines, cyclophosphamide, and carboplatin. Therefore, unless a clearly documented reason for not using such an agent has been demonstrated in a particular patient, a corticosteroid should be added whenever the emetic source is thought to warrant a serotonin antagonist .
Less Active Antiemetics
Antiemetics of lower activity levels include more classic agents such as phenothiazines, butyrophenones, and cannabinoids, all of which have some degree of antiemetic efficacy but greater side effects. When given intravenously, phenothiazines appear to be more active than by other routes but are associated with orthostatic hypotension. For this reason, phenothiazines are not highly recommended for the management of CINV, especially in the elderly. Oral forms of all three of these types of agents exhibit only modest activity and are of a similarly low efficacy. Semisynthetic cannabinoids such as nabilone and levonantradol, the active agent in marijuana (tetrahydrocannabinol, or delta 9-THC), and inhaled marijuana all appear to be of low and equal efficacy, with frequent autonomic side effects. Toxicities include dry mouth, hypotension, and dizziness. Dronabinol (Marinol) may be useful as an adjuvant to other antiemetics. Antianxiety agents such as benzodiazepines have little efficacy as single agents, but seem to work well as adjuncts to antiemetics. They are especially useful as antiemetic adjuncts in patients receiving chemotherapy, which can be a stressful and emotionally charged setting. These drugs may be useful when given to patients with anticipatory emesis, starting one or more days before the next chemotherapy dose. Recommended oral or intravenous doses for lorazepam range from 0.5 to 1.5 mg. Side effects mainly include sedation, especially if the medication is given intravenously.
• Aprepitant—Aprepitant is the first in a new class of antiemetics to be approved for prevention of acute and delayed nausea and vomiting-the NK-1-receptor antagonists. Investigators have identified substance P, an 11-amino acid neuropeptide found in the GI tract and central nervous system that has been shown to elicit vomiting in animal models. Substance P binds to the neuroreceptor NK-1, and blocking this receptor has been linked to such clinical activity as depression, bladder irritability, inflammatory bowel disease, asthma, and functional GI diseases. NK-1 blockers also demonstrate a wide spectrum of antiemetic activity against numerous emetic stimuli. The combination of aprepitant with a 5HT-3 antagonist and a corticosteroid was evaluated in two large, randomized, double-blinded clinical trials with patients receiving high-dose cisplatin.[ 31] These studies found that the addition of aprepitant standard therapy produced a statistically significant increase in emesis control in both the acute and delayed phases, compared to standard therapy alone. The most commonly observed side effects of aprepitant are mild and include fatigue, hiccups, constipation, anorexia, and headache (Table 4).[1,13,32]
• Palonosetron—A second new agent, palonosetron, is the first 5-HT3-receptor antagonist to be FDA-approved for the prevention of acute and delayed CINV. Compared to older 5-HT3 receptor antagonists (ie, ondansetron and dolasetron), palonosetron has demonstrated better prevention of both acute and delayed CINV, perhaps due to its higher serotonin- receptor binding affinity (30- to 100-fold) and prolonged half-life (~40 hours). Palonosetron at 0.25 mg IV is indicated for the prevention of acute CINV associated with initial and repeat cycles of moderately and highly emetogenic chemotherapy and for prevention of delayed CINV associated with initial and repeated courses of moderately emetogenic chemotherapy.[ 24] Adverse reactions to palonosetron are similar to that of the other 5-HT3-receptor antagonists (headache, constipation, diarrhea, dizziness, and fatigue).
Drug Treatment Guidelines
With so many possible combinations of antiemetic drugs, not to mention the possible vast array of chemotherapeutic cocktails, how is one to navigate the best course in order to appropriately prevent CINV? In an attempt to simplify currently published antiemetic recommendations, a set of dynamic and evolving guidelines have been constructed (Tables 5 and 6).[1,13]
Nonmedication Treatment Adjuncts
In addition to standardized pharmacologic approaches to CINV prevention and treatment, now more than ever, our patients have access to a multitude of nonpharmacologic options. Once considered taboo and unsubstantiated, these modalities are undeniably accessible to our patients and for some are valuable adjuvants that complement pharmacologic therapy with the shared goal of improved quality of life. In general, these complementary therapies for nausea and vomiting can be divided into those supporting a patient's body, mind, and/or spirit.[ 33] More physical approaches include osteopathic manipulation, chiropractic treatment, massage therapy, and yoga. Psychological, bioenergetic, or spiritual options with which a patient may find improved control of CINV include such modalities as hypnosis, biofeedback, guided imagery, reiki therapy, relaxation therapy, cognitive therapy, music therapy, and prayer. Some oncology centers offer mind/body approaches as adjuvants to reduce nausea. Both acupuncture and acupressure for CINV have been studied in multiple clinical trials. A recent pediatric study from Croatia (N = 120) demonstrated no statistically significant difference between laser acupuncture and metoclopramide in the occurrence and timing of postoperative nausea and vomiting (P < .001).[36-38] In another study, acupressure showed greater control in decreasing nausea when used as an adjunct to antiemetics (N = 739).[36,37]
Hope for the Future
For the patient facing the possibility of chemotherapy-related nausea and vomiting, the future is hopeful. With the trend toward increased knowledge and understanding of the pathophysiology of emesis, new antiemetic agents, a focus on prevention, and an openness to complementary adjuvants for symptom control, the future of the CINV guideline recommendations will continue to evolve. As clinicians, our goal is to provide patients with state-of-the-art therapy to prevent chemotherapy-induced emesis. This will be accomplished through the development of practical, user-friendly guidelines and an awareness of the complementary adjuvant options that are readily accessible. Until all patients are able to achieve complete control of chemotherapyrelated nausea and vomiting, the search for new mechanisms, new agents, and improved quality of life will continue.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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