Chemotherapy-induced nausea and vomiting (CINV)

It is the result of activation from either the gastrointestinal tract or the central nervous system through stimulation of vagal afferents.

These interactions activate the dorsal vagal complex which coordinate neurons to produce the physical aspects of CINV.

The two major neurotransmitters involved in CINV are serotonin and substance P.

Enterchromaffin cells in the G.I. tract display 5HT3 receptors which blind with serotonin to stimulate vagal afferents within the G.I. tract and CNS to produce nausea and vomiting.

The area poststrema and chemoreceptor trigger zone, located in the medulla, respond to toxic stimuli and activate the dorsal vagal complex.

NK-1 receptors are dense in the CNS.

Substance P is released in response to noxious stimuli and has a very high binding affinity for NK-1 receptors.

This binding also accounts for the several downstream signals which activate the emetic reflex.

Remains the most distressing side effects of chemotherapy.

Two primary risk factors for patients receiving chemotherapy and CINV are: patient-specific risk factors and chemotherapy drug risk factors.

Even with proper treatment for emesis, only 53% of patients report chemotherapy induced nausea had no impact on their daily lives and 73% reported no impact due to vomiting (Tavoreth R).

Components include the vomiting center in the medulla oblongata, the area postrema which is the chemoreceptor trigger zone, and the visceral afferents in the gastrointestinal tract.

Emetogenic potential of chemotherapy are defined as high, moderate low or minimal.

In the absence of antiemetic prophylaxis proportion of patients that experience acute emesis : is at least 90% with high risk agents, 30-90% with moderate risk agents, 10-30% of low risk agents, and 10% of patients with minimal risk.

Delayed nausea and vomiting is a major problem in patients receiving highly emetogenic chemotherapy, as it is an underestimated process.

Acute emesis associated with either highly emetogenic chemotherapy or moderately emetogenic chemotherapy this preventable I. 50-75% and 75-90% of patients, respectively (Cohen L et al).

Especially common and pronounced with DNA alkylating agents, such as cyclophosphamide, cis-platinum, and carmustine.

Duration versus severity of CINV has the greatest impact on quality of life.

Vomiting Center refers to a cluster of normal in the dorsal lateral reticular formation near the nucleus tractus soliarius of the brain stem medulla, and a nearby spongiform, circumfventricular chemotherapy receptor trigger zone in the area postrema.

Vomiting occurs because chemical messages from the bloodstream and the CSF reach the vomiting center via the chemoreceptor trigger zone, and from no oral signals from vagal afferent fibers, which terminate in nucleus tractus solitarius at project to the vomiting center.

The nucleus tractus solitarius plays an important role in nausea by influencing taste, cough, gagging, salivation, blood motility, swallowing, secretions, and the state of arousal.

Categorized as anticipatory, before treatment, acute, occurring within minutes to hours after the start of treatment, delayed, more than 24 hours after the start of therapy, breakthrough, occurring despite prophylactic treatment, and refractory, recurring in future cycles.

Postchemotherapy nausea divided into acute nausea, which develops within 18-24 hours after infusion and delayed nausea which occurs on day 2 or later after treatment.

Delayed nausea may persist for longer than 5 days depending on the anti-neoplastic agent utilized.

Susceptibility increased with female gender, young age, low alcohol intake, increased anxiety levels, and history of motion sickness.

CINV is the most significant side effect from a patient’s perspective.

70-80% of patients undergoing chemotherapy have emesis and 10-44% experience anticipatory emesis.

in a study of 151 patients from 10 oncology centers 67% experienced either acute or delayed CINV during that first chemotherapy cycle (Cohen L et al).

CINV results from interplay of peripheral and central mechanisms involving multiple neurotransmitters such as serotonin, substance P, dopamine, acetylcholine, histamine, GABA and receptors including 5-HT3, cannabinoid-2and NK1.

The limbic system and the cerebral cortex and emotional responses and memory to CINV.

Serotonin release and binding at 5-HT3 and NK1 receptor signaling pathways may allow synergistic action between 5-HT3 and NK1 receptor antagonists in controlling CINV.

Chemotherapy damages enterochromaffin cells in the G.I. tract, causes a release of serotonin, and then it binds to 5-hydroxytryptamine-3 (5-HT 3) receptors on the cabal afferents triggering sensory inputs that project from the G.I. tract to the emetic center of the brainstem.

The area postrema in the chemo receptor trigger zone (CTZ) is also activated by vagal afferent fibers.

Chemotherapy receptors in the area postrema are found outside the blood brain barrier, and can be directly activated by blood borne chemotherapy drugs.

Chemoreceptors in the area postrema can be activated by transmitters which include serotonin, dopamine, and substance P.

Studies suggest delayed CINV is more common than acute CINV, and anticipatory CINV occurs less often.

Nausea is frequently more common than vomiting, and clinically is more significant for patients.

In a prospective study more than 35% of patients experienced acute nausea, and only 13% experienced acute vomiting (Grunberg SM et al).

Percentage of delayed CINV higher than acute CINV in patients given proper antiemetic care (Bloechl-Daum B).

Increased risk in patients with previous chemotherapy induced nausea and vomiting and in those with pregnancy induced nausea and vomiting.

Can cause weakness, weight loss, electrolyte abnormalities, dehydration, anorexia, esophageal tears, fractures and wound dehiscence.

Incidence and severity are influenced by the specific chemotherapeutic agents use, dosage, schedule, route of administration and drug combinations.

The most emetogenic agents are cisplatin (greater than 90% risk), carboplatin (60-90% risk) and cyclophosphamide (30-60% risk).

Agents uses for CINV include 5 hydroxytryptamine3 (5-HT3) receptor antagonists, corticosteroids, neuroknin-1 (NK – 1) receptor antagonists and olanzapine.

When combined with dexamethasone olanzapine has efficacy in chemotherapy induced nausea and vomiting.

Olanzapine 10 mg/ day times three days is effective for breakthrough nausea and vomiting in patients with chemotherapy induced nausea and vomiting.

A combination of dexamethasone, a5-HT3RA and an NK1RA is an appropriate preventive regimen in patients receiving highly emetogenic chemotherapy.

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