Prevention and treatment of CINV in adult patients receiving cancer chemotherapy will be reviewed here. The pathophysiology of CINV is. A range of non-drug treatment strategies exist for the management of CINV, including lifestyle. With the correct use of antiemetics, CINV can be prevented in almost 70% to up to 80% of patients. Treatment guidelines are useful tools that enable physicians.
Is and Is What It Treated? CINV How
This article reviews the current therapies available for the prevention and treatment of CINV. Neurophysiology CINV represents a wide range of symptoms, from mild, queasy nausea to repetitive vomiting and retching. Acute symptoms can begin within minutes of the administration of chemotherapy, but delayed symptoms can also last for many days afterward. Anticipatory CINV can also occur before chemotherapy administration, as a result of a conditioned response to poor emetic control in previous cycles of chemotherapy.
Acute CINV is described as symptoms occurring within the first 24 hours after chemotherapy. Delayed CINV is experienced by patients after the acute phase; these nausea and vomiting symptoms usually peak at about 2 to 3 days after chemotherapy but may last for several days longer. In addition to chemotherapy, many other medical conditions can lead to nausea and vomiting in patients with cancer.
These include hypercalcemia, gastroparesis, gastrointestinal reflux, brain metastases, infections, and many others. Many medications used by patients with cancer can lead to nausea and vomiting, including anti biotics, antifungals, opiate analgesics, and others. It is important to consider these other causes and treat them appropriately, even though they may coincide with CINV. In the classically described pathway, the toxin exposure is detected by the chemoreceptor trigger zone in the CNS, as well as via the enterochromaffin cells in the gastrointestinal tract.
In addition, signals from the cerebral cortex, the limbic system, and the vestibular systems can trigger or accentuate the emetic response. In reaction to these signals, the vomiting center of the CNS activates the emetic response, which includes salivation, contraction of the abdominal muscles, relaxation of the esophageal sphincter, and contraction of the stomach muscles, as well as tachycardia, dizziness, and sweating.
The transmission of the vomiting signals seen with CINV involves multiple neurotransmitters and receptors. The predominant receptors are the serotonin 5-hydroxytryptamine type-3 5-HT3 receptor antagonists, neurokinin-1 NK1 antagonists, and dopamine receptors. Additional neurotransmitters involved include corticosteroid, endogenous cannabinoids, GABA, acetylcholine, and histamine.
The activation or inhibition of these neurotransmitters forms the basis of pharmacologic therapy for CINV. Because multiple neurotransmitters are involved in this process, multiple antiemetic medications are necessary for the maximal prevention and treatment of CINV. The primary determinant of the prevalence of CINV is the inherent emetogenicity of the chemotherapy agents administered. The emetogenicity of chemotherapy agents has been classified into 4 categories.
Table 1 lists the emetogenicity of various chemotherapy agents given by injection. The characteristics of CINV seen with oral chemotherapy agents are different with regard to onset, duration, and severity. Table 2 lists the emetogenic level seen with oral chemotherapy agents.
In addition to the emetogenicity, other chemotherapy- related risk factors include high doses, fast infusions, and multiday chemotherapy administration. Because most chemotherapy regimens use more than 1 antineoplastic agent given on a single day, it is difficult to predict the emetogenicity of these combination regimens. It is recommended that the antiemetic regimen be designed to be consistent with the highest emetogenicity associated with the chemotherapy agents given on each day.
The 5-HT3 receptor antagonists are effective anti - emetic agents associated with minimal adverse effects. These agents block serotonin release from the gastrointestinal tract in addition to blocking serotonin receptors in the CNS. When initially approved in the early s, the 5-HT3 antagonists became the first highly active antiemetics that did not have substantial adverse effects.
The 4 agents in this class—dolasetron, granisetron, ondansetron, and the most recently approved palonosetron—are available in a variety of dosage forms in adults Table 3. The 5-HT3 antagonists are more potent as antiemetic agents than antinausea medications. These agents demonstrate a plateau effect: For patients who can take oral medications, oral therapy is as effective as intravenous IV dosing.
The 5-HT3 antagonists are well tolerated and have few adverse effects. The most often reported side effects include headache, constipation, and diarrhea. It is unclear what the true incidence of adverse events is for the different 5-HT3 antagonists, because these are likely underreported. The FDA has added warnings to the label of ondansetron against the use of the drug by patients with a long QT syndrome and is recommending electrocardiographic monitoring for patients at high risk for this event—those with electrolyte abnormalities, congestive heart failure, or bradyarrhythmias, and patients using concomitant medications that can increase the QTc interval.
For patients without underlying cardiac rhythm disorders or concurrent treatment with other medications that prolong the QTc interval, it is not clear how clinically significant this potential adverse effect is.
It is generally accepted that there are no substantial differences in antiemetic efficacy among the 5-HT3 antagonists, except for palonosetron. Since then, several studies have provided information that further delineates the effects of palonosetron. Corticosteroids Corticosteroids, and dexamethasone in particular, have long been used for the prevention and treatment of CINV. Despite the widespread use of corticosteroids, their precise antiemetic mechanism of action is still unclear. The potential mechanisms may include activation of glucocorticoid receptors in the CNS, decreased release of serotonin, inhibition of prostaglandin synthesis in the cerebral cortex, and alteration of cortical input into the emetic center in the CNS.
Dexamethasone is active in the acute and the delayed phases of CINV. The short-term use of dexamethasone in doses used in CINV is usually well tolerated, although the drug is sometimes underutilized, because of concern for its associated adverse effects. Hyperglycemia is often seen in patients with preexisting or undiagnosed diabetes.
In some patients, the hyperglycemic effect is significant enough to warrant additional glucose monitoring or alterations of antidiabetic medications. The appropriate dexamethasone dose depends on the emetogenicity of the chemotherapy and on whether an NK1 antagonist is coadministered. One group of researchers explored the dose—response relationship of dexamethasone in the context of highly emetogenic chemotherapy, showing that the mg and mg doses of the drug were associated with a higher complete response rate than the 4-mg and 8-mg doses.
The dose and schedule of dexamethasone should be modified if a patient will also receive an NK1 antagonist. Aprepitant and fosaprepitant inhibit the cytochrome CY P 3A4—based metabolism of dexamethasone and result in an approximately 2-fold increase in the area under the curve AUC of dexamethasone. Overall, dexamethasone doses are reduced by half if used concurrently with aprepitant. Available CINV guidelines differ slightly in their recommendations for dexamethasone dose.
For regimens with a high risk of delayed CINV, oral dexamethasone 8 mg daily or twice daily for 2 to 3 days is recommended, depending on whether an NK1 antagonist is also given. All patients in the 2 studies combined received IV palonosetron 0. The patients in the control arms of both studies also received oral dexamethasone on days 2 and 3 8 mg daily in one study and 4 mg twice daily in the other study.
How - ever, in one study, the benefit was most apparent in patients receiving chemotherapy other than anthracycline- cyclophosphamide regimens, and in the other study there was a trend toward better nausea control on day 3 with the 3-day dexamethasone regimen.
Aprepitant is the NK1 antagonist administered orally. Fosaprepitant is a prodrug of aprepitant, administered intravenously. In addition to acute, delayed and anticipatory CINV, patients can also experience breakthrough or refractory CINV, which occurs despite prophylactic antiemetic administrations. The pathophysiology of CINV is not entirely understood, however it is thought to have many contributing pathways. Vomiting or emesis occurs when the vomiting center VC , located in the medulla near the respiratory center on the floor of the fourth ventricle, is activated.
Activation of the VC can arise from pathways in the gastrointestinal GI tract, chemoreceptor trigger zone CTZ , vestibular apparatus, cerebral cortex or a combination of these pathways Camp-Sorrell, The VC is sensitive to several neurotransmitters that are released through each pathway.
Activation from the vestibular-cerebellar pathway, a result of motion sickness or when rapid changes in motion occur, is not directly involved in CINV. When rapidly dividing enterochromaffin cells located in the GI tract are damaged, serotonin is released and binds to vagal afferent receptors that stimulate emesis through the CTZ or directly through the VC.
The CTZ is a highly vascular organ that is not confined to the blood-brain barrier and is therefore vulnerable to exposure to chemotherapy from the blood as well as cerebral spinal fluid Wickham, Activation of the VC directly or through the CTZ results in stimulation of the salivation and respiratory centers as well as control of the pharyngeal, GI and abdominal muscles.
Noradrenaline, somatostatin, enkephalin, acetylcholine, aminobutyric acid, vasopressin and cortisol can also induced vomiting through the CTZ. Though the VC has many neurotransmitter receptors it is most sensitive to muscarinic and dopamine Murphy-Ende, Research has primarily focused on the pathophysiology of acute and delayed CINV, thus the pathophysiology of nausea as a sole entity is less known.
It is thought that nausea is mediated by the autonomic nervous system. Nausea can be described as an unpleasant or queasy feeling causing a desire to vomit. It is important to note that nausea is not always accompanied by vomiting. Clinical manifestations that may accompany nausea include tachycardia, perspiration, light-headedness, dizziness, pallor, excess salivation, anorexia and weakness.
Nausea and vomiting in cancer patients can be multi-factorial. Evaluation of symptoms should reflect this. Nausea and vomiting can have structural, psychological, chemical, metabolic or a combination of origins. When evaluating cancer patients with suspected CINV, causes such as pain, anxiety, hepatosplenomegaly, bowel obstruction, metastasis or increased ICP should also be considered.
Immunocompromised and elderly patients should also be evaluated for bacterial or viral gastroenteritis as these populations may be more vulnerable to an infectious process. It is crucial to illicit onset and duration as well as any potential associated, aggravating or relieving symptoms.
Bowel Obstruction Hepatosplenomegaly Brain metastasis. Oncology nurses possess the ability to educate patients undergoing potentially emetogenic therapy regarding possible risks and risk modifications, non-pharmacologic treatment and potential side effects from prescribed antiemetics.
Assessment, communication and education are key nursing roles in the successful treatment of CINV. These startling statistics emphasize the importance of accurate assessment and communication.
Oncology nurses should complete a thorough history, review of systems and physical exam. Past medical history should include cancer diagnosis and all past and current medical conditions.
Review of systems assessment should include all body systems as this can narrow the field of differential diagnoses. Focused nursing physical assessment should include vital signs, evaluation for orthostatic hypotension, assessment of fluid status measuring output, assessing for edema and monitoring daily weights , pain, manifestations of electrolyte imbalance malaise, fatigue, weakness, palpitations, paresthesias or muscle cramps and manifestations of metabolic alkalosis impaired mentation, hypotension or hypoventation.
Assessment for viral symptoms myalgias, arthralgias, rhinorrhea, headache, stiff neck, vertigo, tinnitus, chest pain, cough and fever as well as neurologic and vestibular symptoms must also be evaluated.
Metastatic brain lesions may cause increased intracranial pressure resulting in acute nausea, vomiting or headache. These symptoms coupled with change in motor or sensory function, personality change or seizures should be evaluated immediately. Recent advances in medications have increased the number of highly effective agents available to treat CINV. These agents work by binding to 5-HT3 receptors both in the peripheral and central nervous system, thus preventing the activation of the CTZ.
Currently fosaprepitant can be administered intravenously on day one of treatment followed by two additional days of oral therapy aprepitant or orally for 3 days. The mechanism by which corticosteroids decrease CINV has yet to be determined; however multiple clinical trials have demonstrated improved outcomes when corticosteroids are used in antiemetic regimens Musso et al. Adjunctive agents such as benzodiazepines and antihistamines may be helpful adjuncts to antiemetic therapy however Kris et al.
Benzodiazepines may be beneficial in patients experiencing anticipatory nausea. Benzodiazepines can be taken orally prior to chemotherapy treatment to reduce anticipatory nausea.
Several guidelines exist that clearly delineate the prevention and treatment of CINV. Adherence to the approved guidelines is essential for improved CINV outcomes. In order to effectively prevent and treat CINV the level of emetogenic potential needs to be correctly identified. Guidelines for the prevention of delayed nausea in HEC are very similar as well and include dexamethasone and aprepitant on days 2 and 3 of the chemotherapy cycle Kris et al.
The ASCO guidelines state that delayed CINV should be prevented with dexamethasone or 5-HT3 antagonist on days , with the exception that any persons receiving cyclophosphamide plus anthracycline should receive antiemetic protection as HEC risk Kris et al. According to ASCO guidelines persons receiving LEC only require dexamethasone prior to treatment while in contrast ONS guidelines do not recommend an antiemetic or any of the following: Acute, delayed, anticipatory and breakthrough nausea continue to negatively impact the QOL of patients receiving cancer therapies.
It is absolutely essential that health care providers accurately acknowledge and treat this issue. In order to improve patient outcomes, health care providers must become familiar with and follow clinical practice guidelines, as well as current evidenced-based information. In the future additional research in non-pharmaceutical interventions would be useful.
Alternative Methods to Treat Nausea and Vomiting from Cancer Chemotherapy
Some people experience CINV within the first few hours of receiving Sometimes, the sights, sounds or smells of the treatment room can trigger this reaction. For this reason, most patients are usually given medication to avoid or prevent such serious side effects before undergoing emetogenic chemotherapy. The FDA has approved intravenous (IV) rolapitant (Varubi) for use in combination with other antiemetic agents to treat delayed.