**4. Risk factors**

The occurrence of CINV can depend on several factors. The risk factors for CINV are both patient- and treatment-related. The most common patient-related risk factors are age, gender, previous motion sickness and/or pregnancy-related N/V and previous CINV. Patients younger than 50 years, females, patients with a history of previous motion sickness and/or pregnancy-related N/V have a greater


#### **Table 2.**

*Classification of antitumoral therapy according to the risk of emesis.*

risk of experiencing CINV. Instead, a previous history of high alcohol consumption is associated with a lower risk of CINV [7–9].

Treatment-related factors and emetogenicity of chemotherapeutic regimens are also relevant. Chemotherapeutic agents are related to various risk of emesis depending on mechanism of action, dose, route and administration in single or combined way. The intrinsic emetogenicity of chemotherapy is the crucial factor to guide the choose of antiemetic treatment. In 2004 an expert consensus conference proposed a classification of chemotherapeutic agents in four categories according to emetogenic potential: high, moderate, low and minimal risk [10]. In the high-risk category, more than 90% could experience CINV without an antiemetic prophylaxis. In the moderate-risk category the potential experience of CINV involves 30–90% of patients. In the low- and minimal risk less than 30% and 10% respectively of cancer patients experience CINV (**Table 2**) [11].

## **5. Physiopathology**

The mechanisms of emesis are not well defined. The physiopathology of CINV includes both central nervous and peripheral system pathways and it is different in acute, delayed and anticipatory setting. The mechanisms inducing CINV have gradually been investigated over the past 60 years. In the 1950s the first hypothesis by Wang and Borison was the existence of a central site called 'vomiting center' located in the medulla processing all the afferent impulses to generate emesis [12]. The presence of some neuronal areas located within medulla coordinating the emetic reflex is now a more realistic hypothesis. All the neuronal cells involved in the series of events occurring during CINV have been called 'central pattern generator' [13]. Three primary components have been found out in the physiopathology of CINV: chemoreceptor trigger zone (CTZ), abdominal vagal afferents and neurotransmitters. After exposure to chemotherapy, the emetic reflex involves two primary sources of afferent input to neuronal areas: abdominal vagal afferents and area postrema, a structure located in the caudal end of the fourth ventricle [14, 15]. 5-hydroxytryptamine 3 (5-HT3), neurokinin-1 (NK1) and cholecystokinin-1 receptors located in the terminal ends of the vagal afferents are close to enteroendocrine cell into the gastrointestinal mucosa of the proximal small intestine. Chemotherapeutic agents stimulate enteroendocrine cells to release some mediators such as 5-hydroxytryptamine, substance P and cholecystokinin which bind to the specific receptors on the close vagal fibers. The afferent impulse reaches the dorsal brain stem through the nucleus of the solitary tract. Among the various receptors, 5-HT3 are considered the most active in acute emesis. In summary, in acute CINV chemotherapeutic agents release free radicals stimulating enterochromaffin cells in the peripheral gastrointestinal tract with subsequent release of serotonin. Serotonin binds 5-HT3 receptors through intestinal vagal afferent nerves and nucleus of the solitary tract and reaches the central nervous system. In delayed CINV the physiologic way is similar but involves less frequently 5-HT3 and more frequently NK1 receptors respectively. In delayed CINV chemotherapeutic agents induce the release of substance P from the neuronal cells in the central and peripheral nervous system. Substance P binds NK1 receptors in the nucleus of solitary tract and led the afferent impulse to central nervous system.

The second pathway potentially involved in the emetic reflex include area postrema. In this region of the brain the blood–brain barrier is more permeable so it is accessible to afferent impulses in either blood or cerebrospinal fluid. This area has commonly been called 'chemoreceptor trigger zone'. This region has afferent and efferent connections with underlying structures, the subnucleous gelatinosus and

**153**

*Chemotherapy-Induced Nausea and Vomiting DOI: http://dx.doi.org/10.5772/intechopen.96194*

agents can also induce emesis binding at this site.

noids have been recently evaluated to treat refractory CINV.

prevention of acute and delayed CINV [7, 17–19].

antiemetic protocols is similar for the various guidelines.

**6. Management**

**6.1 5-HT3 antagonists**

nucleus of solitary tract, receiving vagal afferent fibers from the gastrointestinal mucosa. Metabolites and peptides released under the effect of chemotherapeutic

The clinical role of neurotransmitters has been longer investigated in the past 30 years. The first interest was focused on dopamine, more recently on 5-HT and substance P. Dopaminergic antagonists are the first investigated antiemetic agents [16]. The 5-HT3 receptor antagonists are currently the single most effective class of antiemetics for prevention and treatment of acute CINV. These receptors are located both in central sites such as area postrema and nucleus of solitary tract and in peripheral sites such as vagal afferents. The blockage of 5-HT3 receptor is the most effective mechanism of antiemetic treatment. NK1 receptors are also located both in area postrema and nucleus of solitary tract and in the gastrointestinal mucosa. This evidence suggests that NK1 receptor antagonists plays a central role in prevention and treatment of CINV similar to 5-HT3 receptor antagonists. Endocannabinoids have been more recently investigated as relevant neurotransmitters inducing N/V. The endogenous cannabinoids are agonistic antiemetic agents. Synthetic cannabi-

Anticipatory CINV occurs as a response to a previous experience of CINV. A sensory feeling related to the first administration of chemotherapy led the patient to associate that feeling with N/V. Subsequent exposure to that feeling triggers the response of N/V. Anticipatory CINV can be effectively avoided with an adequate

Antiemetic guidelines are published by all the cancer organizations including American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO) and the Multinational Association of Supportive Care in Cancer (MASCC). There are some differences among the guidelines particularly in the choice of the preferred 5-HT3 receptor antagonist and the use of cannabinoids. The general scheme for

Prevention of CINV is the primary treatment to avoid subsequent episodes of CINV and anticipatory CINV. Due to physiopathology of CINV, 5-HT3 and NK1 receptor antagonists are the main classes of drugs Management include also both pharmacologic and nonpharmacologic agents such as steroids, dopamine antagonists, benzodiazepines, cannabinoids, antipsychotics. The primary issue is the prevention and treatment of moderately and highly emetogenic chemotherapy.

Selective 5-HT3 receptor antagonists have revolutionized the management of CINV. They are indicated in preventing and treating N/V induced by chemotherapy with moderate and high emetic potential. The 5-HT3 receptor antagonists include both first-generation drugs such as ondansetron (Zofran), dolasetron (Anzemet) and granisetron (Kytril) with half-life between 3–9 hours and second-generation drugs such as palonosetron (Aloxi) with half-life of approximately 40 hours. According to their half-life they are used in different indication with more use in acute CINV for first-generation drugs and delayed CINV for second-generation drugs. The first-generation antiemetic drugs are equivalent in efficacy [20–22] and they have few adverse events. The most common adverse events of 5-HT3 receptor antagonist include headache, constipation, transient high levels of hepatic enzymes

#### *Chemotherapy-Induced Nausea and Vomiting DOI: http://dx.doi.org/10.5772/intechopen.96194*

*Suggestions for Addressing Clinical and Non-Clinical Issues in Palliative Care*

tively of cancer patients experience CINV (**Table 2**) [11].

tract and led the afferent impulse to central nervous system.

The second pathway potentially involved in the emetic reflex include area postrema. In this region of the brain the blood–brain barrier is more permeable so it is accessible to afferent impulses in either blood or cerebrospinal fluid. This area has commonly been called 'chemoreceptor trigger zone'. This region has afferent and efferent connections with underlying structures, the subnucleous gelatinosus and

**5. Physiopathology**

is associated with a lower risk of CINV [7–9].

risk of experiencing CINV. Instead, a previous history of high alcohol consumption

Treatment-related factors and emetogenicity of chemotherapeutic regimens are also relevant. Chemotherapeutic agents are related to various risk of emesis depending on mechanism of action, dose, route and administration in single or combined way. The intrinsic emetogenicity of chemotherapy is the crucial factor to guide the choose of antiemetic treatment. In 2004 an expert consensus conference proposed a classification of chemotherapeutic agents in four categories according to emetogenic potential: high, moderate, low and minimal risk [10]. In the high-risk category, more than 90% could experience CINV without an antiemetic prophylaxis. In the moderate-risk category the potential experience of CINV involves 30–90% of patients. In the low- and minimal risk less than 30% and 10% respec-

The mechanisms of emesis are not well defined. The physiopathology of CINV includes both central nervous and peripheral system pathways and it is different in acute, delayed and anticipatory setting. The mechanisms inducing CINV have gradually been investigated over the past 60 years. In the 1950s the first hypothesis by Wang and Borison was the existence of a central site called 'vomiting center' located in the medulla processing all the afferent impulses to generate emesis [12]. The presence of some neuronal areas located within medulla coordinating the emetic reflex is now a more realistic hypothesis. All the neuronal cells involved in the series of events occurring during CINV have been called 'central pattern generator' [13]. Three primary components have been found out in the physiopathology of CINV: chemoreceptor trigger zone (CTZ), abdominal vagal afferents and neurotransmitters. After exposure to chemotherapy, the emetic reflex involves two primary sources of afferent input to neuronal areas: abdominal vagal afferents and area postrema, a structure located in the caudal end of the fourth ventricle [14, 15]. 5-hydroxytryptamine 3 (5-HT3), neurokinin-1 (NK1) and cholecystokinin-1 receptors located in the terminal ends of the vagal afferents are close to enteroendocrine cell into the gastrointestinal mucosa of the proximal small intestine. Chemotherapeutic agents stimulate enteroendocrine cells to release some mediators such as 5-hydroxytryptamine, substance P and cholecystokinin which bind to the specific receptors on the close vagal fibers. The afferent impulse reaches the dorsal brain stem through the nucleus of the solitary tract. Among the various receptors, 5-HT3 are considered the most active in acute emesis. In summary, in acute CINV chemotherapeutic agents release free radicals stimulating enterochromaffin cells in the peripheral gastrointestinal tract with subsequent release of serotonin. Serotonin binds 5-HT3 receptors through intestinal vagal afferent nerves and nucleus of the solitary tract and reaches the central nervous system. In delayed CINV the physiologic way is similar but involves less frequently 5-HT3 and more frequently NK1 receptors respectively. In delayed CINV chemotherapeutic agents induce the release of substance P from the neuronal cells in the central and peripheral nervous system. Substance P binds NK1 receptors in the nucleus of solitary

**152**

nucleus of solitary tract, receiving vagal afferent fibers from the gastrointestinal mucosa. Metabolites and peptides released under the effect of chemotherapeutic agents can also induce emesis binding at this site.

The clinical role of neurotransmitters has been longer investigated in the past 30 years. The first interest was focused on dopamine, more recently on 5-HT and substance P. Dopaminergic antagonists are the first investigated antiemetic agents [16]. The 5-HT3 receptor antagonists are currently the single most effective class of antiemetics for prevention and treatment of acute CINV. These receptors are located both in central sites such as area postrema and nucleus of solitary tract and in peripheral sites such as vagal afferents. The blockage of 5-HT3 receptor is the most effective mechanism of antiemetic treatment. NK1 receptors are also located both in area postrema and nucleus of solitary tract and in the gastrointestinal mucosa. This evidence suggests that NK1 receptor antagonists plays a central role in prevention and treatment of CINV similar to 5-HT3 receptor antagonists. Endocannabinoids have been more recently investigated as relevant neurotransmitters inducing N/V. The endogenous cannabinoids are agonistic antiemetic agents. Synthetic cannabinoids have been recently evaluated to treat refractory CINV.

Anticipatory CINV occurs as a response to a previous experience of CINV. A sensory feeling related to the first administration of chemotherapy led the patient to associate that feeling with N/V. Subsequent exposure to that feeling triggers the response of N/V. Anticipatory CINV can be effectively avoided with an adequate prevention of acute and delayed CINV [7, 17–19].
