ABSTRACT: 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.
A practical issue in every oncology practice is the management of chemotherapyinduced nausea and vomiting (CINV). For the patient it is a quality-of-life issue, and for the medical team caring for the patient, the importance of addressing CINV can not be overstressed. As new drugs such as palonosetron(Drug information on palonosetron) (Aloxi) and aprepitant (Emend) emerge, we as clinicians can best serve our patients with an improved understanding of the pathophysiology of CINV. In light of the mulitfactorial nature of CINV, it is also important to be comfortable with evaluation and diagnosis of this debilitating syndrome. In addition to the pharmacologic approaches, many complementary and integrated modalities may be options for the person with CINV. Future progress in CINV management must include a better understanding of its etiology and a focus on prevention in order to offer maximal symptom control.
Definitions and Prevalence
Nausea is a symptom. It is a subjective, unpleasant experience associated with flushing, tachycardia, and the urge to vomit. Vomiting is a physical phenomenon that involves contraction of the abdominal muscles, descent of the diaphragm, and expulsion of stomach contents. As a selfprotective mechanism, vomiting can sometimes expel noxious substances from the body. Approximately 70% to 80% of all patients who receive chemotherapy experience nausea and vomiting. Anticipatory nausea and vomiting are experienced by approximately 10% to 40% of patients who receive chemotherapy. Nausea and vomiting remain two of patients' most feared effects of cancer treatment, and few side effects of chemotherapy are as universally reported. One early study from 1983 found that vomiting and nausea were the first and second most severe effects of chemotherapy, respectively. Nausea and vomiting consistently rank among the top three reported side effects, along with alopecia. Additionally, many other reported medical side effects, such as weight loss (ranked as number 11), loss of appetite (number 16), and increased thirst (number 37), can result from nausea and vomiting.
Quality of life is significantly affected by CINV. Cancer and its treatment are often quite traumatic for patients, frequently resulting in dramatic changes for the patient's psychology and family, social, and work situations. The acute effects of vomiting are frequently outweighed by the effects of nausea. Many physicians believe that nausea is more devastating than vomiting for the patient's quality of life. Patients who have one to two episodes of vomiting experience almost as much disruption of health-related quality of life as those who have more than two episodes. Fortunately health-related quality-oflife measures seem to return to baseline or higher by 2 to 4 weeks after chemotherapy.[2-4] Unfortunately, patients can still have substantial, disruptive nausea and emesis that clinicians tend to underestimate, especially after they leave the office setting. Chemotherapy-related nausea and vomiting can be disruptive to a person's life in various ways. It can negatively affect a patient's ability to perform activities of daily living. Lindley et al noted degeneration of self-care and decrease in functional, psychological, and physical quality of life in patients receiving intermittent bolus chemotherapy regimens on an outpatient basis (Table 1).
CINV can negatively affect a person's overall health and lead to withdrawal from potentially useful or curative treatment. Loss of appetite is a common effect of nausea and vomiting, as well as a direct effect of some chemotherapeutic agents. Loss of appetite can lead to malnutrition and weight loss or even anorexia. Dehydration is a related concern. The medical team and caregivers must work closely with a dietitian to monitor and help plan strategies to counter these issues. In addition to metabolic derangements and depressed mood, CINV is also associated with fatigue and insomnia. The reasons for this are unclear, but one component of this phenomenon is likely the psychological stress of constant nausea and vomiting. Dyspnea and constipation have also been associated with CINV, although the reasons for these symptoms are not clear.
When assessing the symptoms of nausea and vomiting, the two should be assessed separately. It is recommended that the clinician ask questions about the nausea concerning, for example, the severity and duration, time of day, and other mitigating factors. When assessing emesis, the number of episodes and duration of vomiting, as well as the contents and color of the vomitus (ie, pills, whole undigested food, coffee ground, bilious, etc) can be very helpful information. The inability to keep down other oral therapy such as pain medication can only compound how terrible the patient is feeling from the nausea and vomiting, and alternate medication routes may need to be discussed until nausea and emesis are better controlled. Chemotherapy-induced nausea and vomiting has traditionally been classified into three categories based on the time of onset and pattern of occurrence in relation to the time of chemotherapy administration . These three patterns are acute, delayed, and anticipatory nausea and vomiting. Two additional types associated with lack of symptom control are refractory and breakthrough nausea and vomiting. Chemotherapy-induced nausea and vomiting has traditionally been classified into three categories based on the time of onset and pattern of occurrence in relation to the time of chemotherapy administration . These three patterns are acute, delayed, and anticipatory nausea and vomiting. Two additional types associated with lack of symptom control are refractory and breakthrough nausea and vomiting. Acute CINV refers to nausea or vomiting, or both, that occurs during the first 12 to 24 hours after the administration of chemotherapy; symptoms generally peak after 5 to 6 hours. Cisplatin(Drug information on cisplatin) in high doses (50- 120 mg/m2) will cause emesis in 90% of patients who are not taking prophylactic antiemetics within 24 hours of administration. Most emetogenic chemotherapeutic agents induce emesis about 1 to 2 hours after administration. Acute CINV is the most researched type. The treatment is mainly pharmacologic, and control is still problematic despite improved medication options. Delayed CINV occurs 24 hours after chemotherapy administration. Delayed CINV may last for 6 or 7 days. Acute and delayed CINV are inextricably linked, as the prevention of acute symptoms invariably prevents delayed symptoms. Postulated mechanisms for delayed CINV are different from those for acute CINV. Delayed CINV is well defined when it occurs after high doses of such compounds as carboplatin(Drug information on carboplatin), doxorubicin(Drug information on doxorubicin), epirubicin(Drug information on epirubicin) (Ellence), and anthracyclines. Cisplatin is associated with approximately a 65% to 90% likelihood of causing delayed emesis in the absence of antiemetic prophylaxis. Anticipatory CINV refers to nausea or vomiting as a learned or conditioned response that typically occurs before the administration of chemotherapy. In this situation, patients may be responding to a variety of stimuli such as odor, sight, or sound that is usually associated with a prior experience in which emesis was inadequately controlled. The corresponding psychological mechanism for anticipatory emesis is unknown and is secondary to the direct administration of the chemotherapeutic agent itself. Thus, patients must be given the opportunity to receive the optimal antiemetic regimen with their initial course of chemotherapy to prevent acute CINV as well as anticipatory CINV. Breakthrough nausea and vomiting refers to symptoms that occur despite antiemetic preventive therapy and that necessitate the use of rescue medications. No clear consensus on treatment protocol for this phenomenon exists, although guidelines have been set forth by the National Comprehensive Cancer Network (NCCN).[8,13]
Mechanisms by which chemotherapeutic agents cause nausea and vomiting are complex. The most common is thought to be activation of the chemoreceptor trigger zone (CTZ) located in the area postrema in the floor of the fouth ventricle. Other mechanisms are peripheral stimulation of the gastrointestinal (GI) tract via the vagus nerve, higher centers of the brain stem, and cortex; alterations of taste or smell; and vestibular events via cranial nerve VIII.[1,14] Afferent input from these triggers are perceived by an area in the medulla oblongata known as the vomiting center. Specific neurotranmitters linked to neuroreceptors in the GI tract and CTZ, when activated or irritated by a chemotherapeutic agent, can send input to the vomiting center. Antiemetic therapy targets neuroreceptors located in the peripheral and central nervous system that can activate this central processing area of the brain. The exact neurophysiology of CINV remains unclear. The CTZ is activated via blood or cerebrospinal fluid and invokes the release of various neurotransmitters, which stimulate the vomiting center. Peripherally, when a chemotherapeutic agent causes irritation and damage to GI mucosa, the result is a release of neurotransmitters. These neurotransmitters activate receptors, which in turn send signals to the vomiting center via the vagal afferents. Structurally, parasympathetic stimulation (via cranial nerve X) will increase the secretion rate of almost all GI glands.[1,12,16] Once activated, the vomiting center modulates the efferent transmission to the respiratory, vasomotor, and salivary centers as well as to the abdominal muscles, diaphragm, and esophagus, resulting in emesis. Clearly, the neurophysiology of vomiting is complex and only just beginning to be understood.
Neurotransmitters and Receptors
Numerous neurotransmitters are known to have a role in CINV. These include serotonin, substance P, histamine, dopamine, acetylcholine, gamma- aminobutyric acid(Drug information on aminobutyric acid) (GABA), and enkephalins (Table 2). Any one or a combination of these transmitters may induce vomiting. Other enzymes surround the CTZ, such as adenosine(Drug information on adenosine) triphosphatase, monoamine oxidase, cholinesterase, and catecholamines; however, their role in chemotherapyinduced emesis is unknown.
The serotonin/5-HT3-receptor pathway as well as the substance P/NK1 receptor pathway play major roles in the modulation of CINV. The significance of the serotonin (5-HT3 receptor) pathway was first recognized with high-dose metoclopramide(Drug information on metoclopramide) in decreasing cisplatin-induced emesis. Metoclopramide is a weak antagonist of peripheral 5-HT3 receptors and can stimulate GI motility by increasing acetylcholine release from the cholinergic nerves of the GI tract. The introduction of 5-HT3-receptor antagonists offered an improved treatment option for CINV. Their precise mechanism of action is unknown, but their primary mechanism of action appears to be peripheral. Serotonin receptor antagonists are most effective for acute vomiting but have variable efficacy in delayed CINV, with the exception of a new 5-HT3-receptor blocker, palonosetron. Substance P (mediated by NK-1 receptors) is known to modulate nociception to the brain. High-density NK-1 receptors are located in the regions of the brain implicated in the emetic reflex. The primary mechanism of NK-1-receptor blockade appears to be central, and NK-1 antagonists are effective for both acute and delayed events. These agents augment the antiemetic activity of 5-HT3- receptor antagonists plus corticosteroids in the prevention and treatment of CINV. Histamine receptors are found in abundance in the CTZ; however, H2 antagonists do not work well as antiemetics. H1 antagonists help to alleviate nausea and vomiting induced by vestibular disorders and motion sickness.[ 18] In the recent past, the neurotransmitter that appeared to be most responsible for chemotherapy-induced nausea and vomiting was dopamine(Drug information on dopamine). Many effective antiemetics are dopamine antagonists that may bind specifically to the D2 receptor. However, there is a high degree of variation in the dopamine receptor-binding affinity of these drugs. The action of some drugs that cause nausea and vomiting is affected very little or not at all by the dopamine antagonists. Not all the important receptors in the CTZ are dopaminergic, as the effect of dopamine antagonists is not equal to surgical ablation of the CTZ. It has also been noted that the degree of antiemetic activity of high-dose metoclopramide cannot be explained on the basis of dopamine blockade alone. Metoclopramide is a weak antagonist of peripheral 5-HT3 receptors and can stimulate GI motility by increasing acetylcholine release from the cholinergic nerves of the GI tract. Opiate receptors are also found in the CTZ. It is known that narcotics have mixed emetic and antiemetic effects that are blocked by naloxone. Naloxone also has emetic properties. These facts have led to the proposal of using opiates and enkephalins as antiemetics.
Other mechanisms that may be involved in CINV are effects directly or indirectly on the cerebral cortex, olfactory or gustatory stimuli, and effects on the vestibular system. Animal studies have shown that nitrogen mustard partially causes emesis via direct stimulation of the cerebral cortex. Other evidence indicates that indirect psychological effects can mediate CINV; for example, the risk of nausea and vomiting may increase if the patient's roommate is experiencing nausea or vomiting, and the amount of sleep before receiving chemotherapy may influence whether a patient develops chemotherapy-induced emesis. The importance of taste and odor perception in relation to enhancement of gagging, nausea, and vomiting is well appreciated, although the exact mechanism is unknown. Women who have suffered from hyperemesis during pregnancy show taste damage. In addition to indirectly affecting taste, some chemotherapeutic agents can actually be tasted. In a study of breast cancer patients who received cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil), 36% reported a bitter taste in their mouth. A third of the patients believed this bitter taste led to vomiting. Clearly, changes in taste may contribute to both nausea and vomiting as well as to anorexia. Chemotherapeutic agents can also cause CINV by influencing the vestibular system. Patients with a history of motion sickness or vertigo experience a greater severity, frequency, and duration of nausea and vomiting from chemotherapy than patients who do not experience motion sickness or vertigo. Once again, the mechanism by which effects on the vestibular system may lead to CINV is unknown, but it is postulated that sensory information received by the vestibular system differs from information that was anticipated.