Pathophysiology and prediction of chemotherapy-induced nausea and vomiting

INTRODUCTION — Few side effects of cancer treatment are more feared by the patient than nausea and vomiting. Although nausea and emesis (vomiting and/or retching) can also result from surgery, opiates, or radiotherapy, chemotherapy-induced nausea and vomiting (CINV) is potentially the most severe and most distressing. Although significant progress has been made with the development of a number of effective and well-tolerated antiemetic treatments, CINV remains an important adverse effect of treatment. Emesis can be objectively measured with direct independent observation. Nausea, which often accompanies emesis, is a subjective sensation that requires a patient's self-report to quantitate. The mechanisms underlying chemotherapy-induced nausea are less well understood at present and will not be addressed.

The types of emesis, its pathophysiology, and factors predictive for the development of CINV will be reviewed here. The characteristics of the available antiemetic drugs, the management of CINV, and a general approach to the patient are discussed separately. (See "Prevention of chemotherapy-induced nausea and vomiting in adults" and "Characteristics of antiemetic drugs" and "Approach to the adult with nausea and vomiting".)

TYPES OF EMESIS — Three distinct types of CINV have been defined: acute, delayed, and anticipatory. Recognizing the differences between these types of CINV has important implications for both prevention and management.

Acute emesis — Acute emesis is defined as emesis occurring during the first 24 hours after chemotherapy. In the absence of effective prophylaxis, it most commonly begins within one to two hours of chemotherapy and usually peaks in the first four to six hours. Acute emesis is the most widely studied manifestation of CINV.

Delayed emesis — Emesis occurring more than 24 hours after chemotherapy is classified as delayed. It is best characterized following treatment with high-dose cisplatin. In the absence of antiemetic prophylaxis, delayed emesis after cisplatin peaks at approximately 48 to 72 hours after therapy, then gradually subsides over the next two to three days [1]. While the frequency and number of episodes of emesis may be less during the delayed period compared with acute emesis, the delayed form is less well controlled with current antiemetic medications [2]. Delayed emesis occurs most frequently after cisplatin but can also occur following other agents, including carboplatin, cyclophosphamide, anthracyclines, and oxaliplatin [2,3], and after combinations, such as cyclophosphamide plus an anthracycline.

Anticipatory emesis — Anticipatory emesis is a conditioned response in patients who have developed significant nausea and vomiting during previous cycles of chemotherapy. It can be elicited by a variety of stimuli and cognitive activities in association with subsequent cycles of chemotherapy [4]. As antiemetic control during the initial cycle of chemotherapy has progressively improved, anticipatory emesis has become a less significant clinical problem. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Anticipatory emesis'.)

PATHOPHYSIOLOGY — Considerable progress has been made in elucidating the mechanisms by which chemotherapy initiates the emetic reflex. This understanding includes both the anatomy and neurotransmitters involved in CINV.

Neuroanatomy — Several areas in the central and peripheral nervous systems and gastrointestinal tract are involved in CINV (figure 1). Three areas in the brainstem are thought to play critical roles in the emetic reflex: the central pattern generator (CPG; previously called the "vomiting center") and two areas in the dorsal brainstem called the nucleus tractus solitarius (NTS) and area postrema (AP) [5-8].

●The CPG is an anatomically indistinct collection of receptor and effector nuclei located in the medulla that coordinates the emetic reflex. It appears to coordinate the efferent respiratory, gastrointestinal, and autonomic activity associated with nausea and vomiting and functions as the final effector pathway through which a variety of afferent stimuli can activate emesis [9,10].

●The AP and NTS form a circumventricular structure located at the caudal end of the fourth ventricle. Together, these two areas were previously referred to as the "chemoreceptor trigger zone." This part of the dorsal brain stem lies outside of the blood-brain barrier and is, therefore, accessible to emetic stimuli borne either in the blood or cerebrospinal fluid [6]. The AP/NTS appears to be an important source of afferent input to the CPG and is an important site for muscarinic (M1), dopamine (D2), serotonin (5-hydroxytryptamine [5-HT]), neurokinin-1 (NK1), and histamine (H1) receptors [11,12].

Two other sources of afferent input to the CPG with CINV include higher brainstem and cortical structures, which may play a role in anticipatory emesis, and input from the gastrointestinal tract that is conveyed by the vagus and splanchnic nerves, whose afferents terminate in the NTS in close proximity to or within the AP itself [13,14]. These two areas of the brainstem are referred to collectively as the dorsal vagal complex (figure 1).

Neurotransmitters — Although over 30 neurotransmitters have been associated with the peripheral and central nervous system sites involved in CINV, three neurotransmitters have the most clinical relevance, since therapeutic agents designed to antagonize their action have shown clinical benefit as antiemetics [15]:

●D2

●5-HT

●Substance P

5-HT received significant attention during the 1980s in preclinical studies attempting to elucidate the mechanisms of CINV [16]. These studies led to the development of the type-three 5-HT (5-HT3) receptor antagonists during the early 1990s [17], and these drugs have become a mainstay of current antiemetic therapy for CINV. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

Substance P became a focus for preclinical studies evaluating the emetic reflex beginning in the 1990s. Substance P binds to the NK1 receptors [18], and selective antagonists of the NK1 receptor are potent antiemetics in preclinical models using a variety of emetic stimuli [19]. Subsequent clinical trials in CINV led to the development of aprepitant and fosaprepitant for patients receiving highly emetogenic chemotherapy. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Neurokinin-1 receptor antagonists'.)

Mechanisms — A precise understanding of the mechanisms by which chemotherapy induces emesis remains elusive. Several reviews summarize our current understanding of the pathophysiology of CINV [20-25]. The following figure schematically illustrates potential sites at which chemotherapy is thought to exert its emetic effects (figure 1).

The mechanism that is best supported by research is that chemotherapeutic drugs can cause nausea and vomiting by activating neurotransmitter receptors in the small intestine; afferent fibers then transmit the stimuli to the brainstem, which then sends out efferent signals via the vagus nerve to induce vomiting.

Studies in animal models indicate that the intestinal cell damage produced by chemotherapy initiates the release of 5-HT and other neuroactive agents from enterochromaffin cells. These agents bind to the 5-HT3 receptor and other receptors on the vagal and splanchnic afferent fibers within the wall of the gastrointestinal tract. The stimulated vagal and splanchnic afferents project to the AP/NTS, resulting in activation of the emetic reflex arc.

Current knowledge suggests that the emetic response to chemotherapy can occur through a central and a peripheral pathway, mediated by different neurotransmitters (figure 1) [23,24]:

●The peripheral pathway, which is predominantly mediated by 5-HT and 5-HT3 receptors in the intestinal tract, is associated primarily with acute emesis (that occurring within 24 hours of chemotherapy).

●A central pathway, which is predominantly mediated by Substance P and NK1 receptors and is located primarily in the brain, is activated later and mainly associated with delayed CINV (after 24 hours).

Some chemotherapy agents or their metabolites may interact directly or indirectly with receptors within the AP/NTS, with subsequent activation of the CPG. Furthermore, higher central nervous system centers located in structures in the limbic forebrain, such as the amygdala, may also be a source of some types of emetic stimuli [26].

PREDICTIVE FACTORS — A number of factors have been identified that provide the clinician with a means of predicting the likelihood that CINV will develop in various situations. The most important is the intrinsic emetogenicity of the chemotherapy agent and its mode of administration. Other prognostic factors are related to the patient population, and others are treatment dependent.

Chemotherapy agent — The management of CINV has been greatly facilitated by the development of classification schemes that reflect the likelihood of emesis developing following treatment with a particular agent. A 1997 classification scheme gained broad acceptance and was utilized as the basis for treatment recommendations by guideline panels [27,28]. Chemotherapy agents were divided into five emetogenic levels that were defined by the expected frequency of emesis in the absence of effective antiemetic prophylaxis.

A modification of this schema was proposed at the 2004 Perugia Antiemetic Consensus Guideline meeting [29] and is still in widespread use, although many more chemotherapy agents are now available. Chemotherapy agents were placed into four categories by their emetogenic potential with separate classifications for parenteral and oral agents (table 1 and table 2):

●High – >90 percent risk of emesis

●Moderate – >30 to 90 percent risk of emesis

●Low – 10 to 30 percent risk of emesis

●Minimal – <10 percent risk of emesis

Oral anticancer agents have proven quite challenging to classify by their emetogenic potential as these agents tend to be used in extended regimens of daily use rather than the single bolus administration schedules commonly employed with intravenous agents. The emetogenic classification for oral agents was later revised into a two emetic risk category reflecting the challenges in attempting to precisely characterize the emetogenic potential of the oral agents:

●Moderate or high - >30 percent risk of emesis

●Minimal or low - <30 percent risk of emesis

This schema is utilized in the updated antiemetic guidelines of the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO), the National Comprehensive Cancer Network (NCCN), and the American Society of Clinical Oncology (ASCO) [30-32]. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Estimating the risk of nausea and vomiting'.)

For any given drug, the route and rate of administration, as well as the dose, can also influence emetogenicity [33,34]. For combination regimens, the emetogenic level is determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents. As an example, cyclophosphamide and doxorubicin are both moderately emetogenic agents, but when given together, the regimen is considered to be highly emetogenic [32,35]. The three categories of drugs with the highest therapeutic index for the management of CINV are the type-three 5-hydroxytryptamine (5-HT3) receptor antagonists, the neurokinin-1 (NK1) receptor antagonists, and glucocorticoids (especially dexamethasone). (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on '5-HT3 receptor antagonists' and "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Neurokinin-1 receptor antagonists' and "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Glucocorticoids'.)

Recommendations for antiemetic therapy from expert groups such as ASCO and MASCC/ESMO are generally based only on the estimated emetogenicity of the individual chemotherapy components of the regimen. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Recommendations for specific groups'.)

Patient-related factors — In addition to the specific chemotherapy agent, a number of patient-related factors have been associated with an increased risk of CINV [36-40]. These include the following:

●Emesis with prior chemotherapy increases the risk of CINV. As an example, in a study of 1413 patients, the majority (72 percent) of patients reporting vomiting at the first treatment also reported subsequent vomiting; 31 percent of these patients experienced emesis at all remaining treatments [40]. In contrast, 76 percent of patients who were emesis free at the first treatment remained so for all later treatments.

●Women have an increased risk of CINV compared with men.

●Younger patients are more susceptible to CINV than older patients.

●Patients with a significant history of alcohol consumption are less susceptible to CINV than those without such a history.

●Rapid metabolizers of certain 5-HT3 receptor antagonists are more susceptible to severe CINV [41], and certain polymorphisms in the 5-HT3 receptor can also confer a greater risk of CINV [42].

●Patients who experience acute emesis with chemotherapy are significantly more likely to have delayed emesis.

●Anticipatory emesis occurs in patients who have had poor control of either acute or delayed emesis with prior chemotherapy [4,43]. It has been suggested that a history of motion sickness may predispose to anticipatory emesis [44].

Prediction models — Predictive models for CINV that incorporate personal and treatment characteristics, past history of nausea and vomiting, symptoms present before chemotherapy (including anxiety), and expectations for nausea and vomiting have been developed [45-47]. In one of these, in the initial cohort of 336 chemotherapy-naïve patients receiving chemotherapy with a variety of agents for up to three cycles (286 the initial development cohort and 50 the validation set), a total of five independent variables were found to be significantly associated with acute or delayed emesis [46]. Using a binary classifier of outcomes (complete protection of emesis versus one or more episodes of emesis), younger age, history of past nausea or vomiting (eg, with pregnancy, motion sickness, or vestibular dysfunction), and high levels of anxiety and pain present before chemotherapy were all significantly associated with a higher risk of CINV, while administration of agents with a low or moderate level of emetogenicity was associated with a significantly lower level of CINV. The final prediction model had a sensitivity and specificity of 79 and 50 percent, respectively. The Area under the Receiver Operating Characteristic Curve (AROCC; a standard method for evaluating model performance) was not reported.

The benefit of following risk model-guided (RMG) recommendations for antiemetic prophylaxis was shown in a randomized trial in which 324 patients receiving cyclophosphamide plus an anthracycline for early breast cancer at one of two Canadian cancer centers were randomly assigned to RMG (which took into account type of chemotherapy, age, history of motion and/or morning sickness, low daily alcohol consumption, and prior history of emesis during chemotherapy) versus physician's choice antiemetic prophylaxis [47]. Of the patients in the RMG group, 81 percent received aprepitant at cycle 1 because they were classified as receiving a high-risk combination; in contrast, only 5 percent of the physician's choice group received aprepitant initially. In the acute period, significantly more patients in the RMG group reported complete protection from nausea (54 versus 42 percent) or vomiting (92 versus 82 percent); a similar benefit was noted with delayed nausea (40 versus 31 percent) and vomiting (87 versus 78 percent). Unfortunately the risk-adapted model was not able to identify a true "low-risk" group that would not ultimately require the use of an NK1 receptor antagonist [48].

Whether models such as these provide additional information beyond the estimated emetogenicity potential of the individual chemotherapy agents is unclear. None of these models is ready to be utilized in routine clinical practice.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chemotherapy-induced nausea and vomiting in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Nausea and vomiting with cancer treatment (The Basics)")

SUMMARY

●Types of emesis – Three distinct types of chemotherapy-induced nausea and vomiting (CINV) have been defined: acute, delayed, and anticipatory. Delayed emesis occurs most frequently after cisplatin but can also occur following other agents, including carboplatin, cyclophosphamide, anthracyclines, and oxaliplatin. (See 'Types of emesis' above.)

●Pathophysiology – There are several potential sites at which chemotherapy is thought to exert its emetogenic effects (figure 1). (See 'Pathophysiology' above.)

●Predicting likelihood of nausea and vomiting – A number of factors have been identified that provide the clinician with a means of predicting the likelihood that CINV will develop in various situations, the most important of which is the intrinsic emetogenicity of the chemotherapy agent. Intravenous and orally administered chemotherapy agents can be divided into four and two emetogenic levels, respectively, that are defined by the expected frequency of emesis in the absence of effective antiemetic prophylaxis. (See 'Chemotherapy agent' above.)

This schema is utilized in antiemetic guidelines from the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology, the National Comprehensive Cancer Network, and the American Society of Clinical Oncology. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)