Purpose of This PDQ Summary
Overview

Introduction Classifications

Neurophysiology
General Risk Factors and Etiologies
Anticipatory Nausea and Vomiting

Prevalence Classical Conditioning Variables Correlated with ANV Treatment of ANV

Acute/Delayed Emesis Etiology

Acute Emesis Delayed Emesis

Prevention of Acute/Delayed Emesis

Phenothiazines         Prochlorperazine Butyrophenones         Droperidol and haloperidol Dopamine 2 Antagonists         Metoclopramide 5-HT3 Antagonists         Ondansetron         Granisetron         Dolasetron         Palonosetron         Comparison of agents Substance P Antagonists (NK-1 Receptor Antagonists) Corticosteroids Cannabinoids Benzodiazepines         Lorazepam         Olanzapine Management of Chemotherapy-induced Nausea and Vomiting

Nausea, Vomiting, Constipation, and Bowel Obstruction in Advanced Cancer

Frequency Pathophysiology and Causes Assessment Management Malignant Bowel Obstruction

Nonpharmacologic Management of Nausea and Vomiting
Radiation Therapy

Correlates Prevalence Treatment

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Purpose of This PDQ Summary

This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of nausea and vomiting. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board.

Information about the following is included in this summary:

• Anticipatory nausea and vomiting.
• Acute/delayed nausea and vomiting.
• Chronic nausea and vomiting in patients with advanced cancer.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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Overview

Prevention and control of nausea and vomiting are paramount in the treatment of cancer patients. Nausea and vomiting can result in serious metabolic derangements, nutritional depletion and anorexia, deterioration of patients’ physical and mental status, esophageal tears, fractures, wound dehiscence, withdrawal from potentially useful and curative antineoplastic treatment, and degeneration of self-care and functional ability. Despite advances in pharmacologic and nonpharmacologic management, nausea and vomiting remain two of the more distressing and feared side effects to cancer patients and their families, and incidence may be underestimated by physicians and nurses.[1-5]

Nausea is a subjective phenomenon of an unpleasant, wavelike sensation experienced in the back of the throat and/or the epigastrium that may or may not culminate in vomiting. Vomiting is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching is gastric and esophageal movements of vomiting without expulsion of vomitus and is also referred to as dry heaves.

Various classifications of nausea and vomiting (N&V) have been used,[1,6] including acute, delayed, late or persistent, chronic, anticipatory, breakthrough, or refractory, as well as distinctions related to type of treatment (e.g., chemotherapy- or radiation-induced), and clinical course (e.g., advanced or terminal disease).[7,8] Despite this variety, the most commonly described types are acute, delayed, and anticipatory chemotherapy-induced N&V; and chronic N&V in advanced cancer patients. Although there are no standard definitions, the following are commonly used to classify the different types.

• Acute nausea and vomiting (or emesis): N&V experienced during the first 24-hour period after chemotherapy administration is considered acute N&V.[1]



• Delayed (or late) nausea and vomiting (or emesis): N&V that occurs more than 24 hours after chemotherapy administration is considered delayed, or late, N&V. Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more consecutive days.



• Anticipatory nausea and vomiting (ANV): ANV is nausea and/or vomiting that occur prior to the beginning of a new cycle of chemotherapy, in response to conditioned stimuli such as the smells, sights, and sounds of the treatment room. ANV is a classically conditioned response that typically occurs after three or four prior chemotherapy treatments, following which the person experienced acute or delayed N&V.



• Chronic nausea and vomiting (or emesis) in advanced cancer patients: Chronic nausea and vomiting in the advanced cancer patient is N&V associated with a variety of potential etiologies. A definitive understanding of cause is not well known, nor well researched, but potential causal factors include gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic chemotherapy, and radiation-induced mechanisms.[9]

References

1. Wickham R: Nausea and vomiting. In: Yarbo CH, Frogge MH, Goodman M, eds.: Cancer Symptom Management. 2nd ed. Sudbury, Mass: Jones and Bartlett Publishers, 1999, pp 228-263. 
   
   
2. Coates A, Abraham S, Kaye SB, et al.: On the receiving end--patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 19 (2): 203-8, 1983.  [PUBMED Abstract]
   
   
3. Craig JB, Powell BL: The management of nausea and vomiting in clinical oncology. Am J Med Sci 293 (1): 34-44, 1987.  [PUBMED Abstract]
   
   
4. Passik SD, Kirsh KL, Rosenfeld B, et al.: The changeable nature of patients' fears regarding chemotherapy: implications for palliative care. J Pain Symptom Manage 21 (2): 113-20, 2001.  [PUBMED Abstract]
   
   
5. Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.  [PUBMED Abstract]
   
   
6. Pisters KM, Kris MG: Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 165-199. 
   
   
7. Fallon BG: Nausea and vomiting unrelated to cancer treatment. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 179-189. 
   
   
8. Allan SG: Nausea and vomiting. In: Doyle D, Hanks GW, MacDonald N, eds.: Oxford Textbook of Palliative Medicine. 2nd ed. New York, NY: Oxford University Press, 1998, pp 282-290. 
   
   
9. Schwartzberg L: Chemotherapy-induced nausea and vomiting: state of the art in 2006. J Support Oncol 4 (2 Suppl 1): 3-8, 2006.  [PUBMED Abstract]
   
   

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Neurophysiology

Progress has been made in understanding the neurophysiologic mechanisms that control nausea and vomiting. Both are controlled or mediated by the central nervous system but by different mechanisms. Nausea is mediated through the autonomic nervous system. Vomiting results from the stimulation of a complex reflex that is coordinated by a putative true vomiting center, which may be located in the dorsolateral reticular formation near the medullary respiratory centers. The vomiting center presumably receives convergent afferent stimulation from several central neurologic pathways, including the following:[1,2]

• A chemoreceptor trigger zone (CTZ).



• The cerebral cortex and the limbic system in response to sensory stimulation (particularly smell and taste), psychologic distress, and pain.



• The vestibular-labyrinthine apparatus of the inner ear, in response to body motion.



• Peripheral stimuli from visceral organs and vasculature (via vagal and spinal sympathetic nerves) as a result of exogenous chemicals and endogenous substances that accumulate during inflammation, ischemia, and irritation.

The CTZ is located in the area postrema, one of the circumventricular regions of the brain on the dorsal surface of the medulla oblongata at the caudal end of the fourth ventricle. Unlike vasculature within the blood-brain diffusion barrier, the area postrema is highly vascularized with fenestrated blood vessels, which lack tight junctions (zonae occludentes) between capillary endothelial cells. The CTZ is anatomically specialized to readily sample elements present in the circulating blood and cerebrospinal fluid (CSF).[3,4]

Currently, evidence indicates that acute emesis following chemotherapy is initiated by the release of neurotransmitters from cells that are susceptible to the presence of toxic substances in the blood or CSF. Area postrema cells in the CTZ and enterochromaffin cells within the intestinal mucosa are implicated in initiating and propagating afferent stimuli that ultimately converge on central structures corresponding to a vomiting center. The relative contribution from these multiple pathways culminating in nausea and vomiting symptoms is complex and is postulated to account for the variable emetogenicity (intrinsic emetogenicity and mitigating factors, i.e., dosage, administration route, exposure duration) and emetogenic profile (i.e., time to onset, symptom severity, and duration) of agents.

References

1. Pisters KM, Kris MG: Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 165-199. 
   
   
2. Berger AM, Clark-Snow RA: Nausea and vomiting. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, 2705-2712. 
   
   
3. Andrews PL, Hawthorn J: The neurophysiology of vomiting. Baillieres Clin Gastroenterol 2 (1): 141-68, 1988.  [PUBMED Abstract]
   
   
4. Miller AD, Leslie RA: The area postrema and vomiting. Front Neuroendocrinol 15 (4): 301-20, 1994.  [PUBMED Abstract]
   
   

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General Risk Factors and Etiologies

Not all cancer patients will experience nausea and/or vomiting. The most common causes are emetogenic chemotherapy drugs and radiation therapy to the gastrointestinal (GI) tract, liver, or brain. Several patient characteristics have also been identified. These include incidence and severity of nausea and vomiting (N&V) during past courses of chemotherapy, history of chronic alcohol use, age, and gender. Patients with poor control of N&V during prior chemotherapy cycles are likely to experience N&V in subsequent cycles. N&V is less likely in patients with a history of chronic, high alcohol intake,[1] and more likely in women [2,3] and younger patients (<50 years).[2]

Other possible causes include fluid and electrolyte imbalances such as hypercalcemia, volume depletion, or water intoxication; tumor invasion or growth in the GI tract, liver, or central nervous system, especially the posterior fossa; constipation; certain drugs such as opioids; infection or septicemia; or uremia. The psychological variables of state anxiety (level of anxiety during chemotherapy infusions), and pretreatment expectations for nausea and vomiting (self-fulfilling prophecy) have also been investigated as predictors of posttreatment nausea.[4-9] At present, studies have found mixed results that vary due to different research methods. Better designed studies, however, have found state anxiety and patient expectations for nausea to be predictors of posttreatment nausea, even after controlling for known physiological predictors (susceptibility to nausea during pregnancy and motion sickness) and emetogenic potential of the chemotherapy drugs.[6-8,10,11] It is important to note, however, that patients’ fears and expectations about chemotherapy can be variable and change over time.[12] In a longitudinal study [12] patients’ anticipatory fears of vomiting decreased significantly from pretreatment to a period 3 to 6 months later, particularly when their chemotherapy included antiemetic medications.

Clinicians treating N&V must be alert to all potential causes and factors, especially in cancer patients who may be receiving combinations of several treatments and medications. (Refer to the PDQ summary on Pain for more information on opioid-induced nausea and vomiting.)

References

1. Sullivan JR, Leyden MJ, Bell R: Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion. N Engl J Med 309 (13): 796, 1983.  [PUBMED Abstract]
   
   
2. Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: a review. Ann Oncol 2 (2): 107-14, 1991.  [PUBMED Abstract]
   
   
3. Roila F, Tonato M, Basurto C, et al.: Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 5 (1): 141-9, 1987.  [PUBMED Abstract]
   
   
4. Cassileth BR, Lusk EJ, Bodenheimer BJ, et al.: Chemotherapeutic toxicity--the relationship between patients' pretreatment expectations and posttreatment results. Am J Clin Oncol 8 (5): 419-25, 1985.  [PUBMED Abstract]
   
   
5. Andrykowski MA, Gregg ME: The role of psychological variables in post-chemotherapy nausea: anxiety and expectation. Psychosom Med 54 (1): 48-58, 1992 Jan-Feb.  [PUBMED Abstract]
   
   
6. Jacobsen PB, Andrykowski MA, Redd WH, et al.: Nonpharmacologic factors in the development of posttreatment nausea with adjuvant chemotherapy for breast cancer. Cancer 61 (2): 379-85, 1988.  [PUBMED Abstract]
   
   
7. Haut MW, Beckwith BE, Laurie JA, et al.: Postchemotherapy nausea and vomiting in cancer patients receiving outpatient chemotherapy. Journal of Psychosocial Oncology 9(1): 117-130, 1991. 
   
   
8. Roscoe JA, Hickok JT, Morrow GR: Patient expectations as predictor of chemotherapy-induced nausea. Ann Behav Med 22 (2): 121-6, 2000 Spring.  [PUBMED Abstract]
   
   
9. Hickok JT, Roscoe JA, Morrow GR: The role of patients' expectations in the development of anticipatory nausea related to chemotherapy for cancer. J Pain Symptom Manage 22 (4): 843-50, 2001.  [PUBMED Abstract]
   
   
10. Roscoe JA, Bushunow P, Morrow GR, et al.: Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer 101 (11): 2701-8, 2004.  [PUBMED Abstract]
    
    
11. Higgins SC, Montgomery GH, Bovbjerg DH: Distress before chemotherapy predicts delayed but not acute nausea. Support Care Cancer 15 (2): 171-7, 2007.  [PUBMED Abstract]
    
    
12. Passik SD, Kirsh KL, Rosenfeld B, et al.: The changeable nature of patients' fears regarding chemotherapy: implications for palliative care. J Pain Symptom Manage 21 (2): 113-20, 2001.  [PUBMED Abstract]
    
    

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Anticipatory Nausea and Vomiting

Prevalence

The prevalence of anticipatory nausea and vomiting (ANV) has varied, owing to changing definitions and assessment methods.[1] However, anticipatory nausea (AN) appears to occur in approximately 29% of patients receiving chemotherapy, or about 1:3, while anticipatory vomiting (AV) appears to occur in 11% of patients, or about 1:10.[2] With the introduction of new pharmacologic agents (5-HT₃ receptor antagonists), it was anticipated that the prevalence of ANV might decline; however, studies have shown mixed results. One study found a lower incidence of ANV,[3] and three studies found comparable incidence rates.[2,4,5] It appears that the 5-HT₃ agents reduce postchemotherapy vomiting, but not postchemotherapy nausea,[2,5] and the resulting impact on ANV is unclear.

Although other theoretical mechanisms have been proposed,[6] ANV appears to be best explained by classical conditioning (also known as Pavlovian or respondent conditioning).[7] In classical conditioning, a previously neutral stimulus (e.g., smells of the chemotherapy environment) elicits a conditioned response (e.g., ANV) after a number of prior pairings or learning trials. In cancer chemotherapy the first few chemotherapy infusions are the learning trials. The chemotherapy drugs are the unconditioned stimuli that elicit postchemotherapy nausea and vomiting (in some patients). They are paired with a variety of other neutral, environmental stimuli (e.g., smells of the setting, oncology nurse, chemotherapy room). These previously neutral stimuli then become conditioned stimuli and elicit ANV in future chemotherapy cycles. ANV is not an indication of psychopathology, but rather a learned response that, in other life situations (e.g., food poisoning) results in adaptive avoidance. A variety of correlational studies provide empirical support for classical conditioning. For example, the prevalence of ANV prior to any chemotherapy is very rare, and few patients ever experience ANV without prior postchemotherapy nausea.[8] Also, most studies have found a higher probability of ANV with increasing numbers of chemotherapy infusions, and the intensity of ANV increases as patients get closer to the actual time of their infusion.[9] In one experimental study, it was shown that a novel beverage could become a conditioned stimulus to nausea when paired with several chemotherapy treatments.[10]

Many variables have been investigated as potential factors that correlate with the incidence of ANV in hopes of developing a list of risk factors. There is currently no agreement on which factors predict ANV. A patient with fewer than three of the first eight characteristics listed below, however, is unlikely to develop ANV, and screening following the first chemotherapy infusion could identify those patients at increased risk.[11]

Variables Found to Correlate With ANV

1. Age younger than 50 years.



2. Nausea/vomiting after last chemotherapy session.



3. Posttreatment nausea described as moderate, severe, or intolerable.



4. Posttreatment vomiting described as moderate, severe, or intolerable.



5. Feeling warm or hot all over after last chemotherapy session.



6. Susceptibility to motion sickness.



7. Sweating after last chemotherapy session.



8. Generalized weakness after last chemotherapy session.



9. Female gender.



10. High-state anxiety (anxiety reactive to specific situations).[12,13]



11. Greater reactivity of the autonomic nervous system and slower reaction time.[14]



12. Patient expectations of chemotherapy-related nausea before beginning treatment.[15,16]



13. Percentage of infusions of chemotherapy followed by nausea.[17]



14. Postchemotherapy dizziness.



15. Lightheadedness.



16. Longer latency of onset of posttreatment nausea and vomiting.[18]



17. Emetogenic potential of various chemotherapeutic agents. Patients receiving drugs with a moderate-to-severe potential for posttreatment nausea and vomiting are more likely to develop ANV.[12]



18. Morning sickness during pregnancy.

Antiemetic drugs do not seem to control ANV once it has developed;[2] however, a variety of behavioral interventions have been investigated.[19] These include progressive muscle relaxation with guided imagery,[20] hypnosis,[21] systematic desensitization,[22] electromyography (EMG) and thermal biofeedback,[23] and distraction via the use of video games.[24,25] Progressive muscle relaxation with guided imagery, hypnosis, and systematic desensitization has been studied the most and is the recommended treatment. Referral to a psychologist or other mental health professional with specific training and experience in working with cancer patients is recommended when ANV is identified. The earlier it is identified, the more likely treatment will be effective, and thus early screening and referral are essential. In addition, physicians and nurses underestimate the incidence of chemotherapy-induced nausea and vomiting.[26]

References

1. Andrykowski MA: Defining anticipatory nausea and vomiting: differences among cancer chemotherapy patients who report pretreatment nausea. J Behav Med 11 (1): 59-69, 1988.  [PUBMED Abstract]
   
   
2. Morrow GR, Roscoe JA, Kirshner JJ, et al.: Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 6 (3): 244-7, 1998.  [PUBMED Abstract]
   
   
3. Aapro MS, Kirchner V, Terrey JP: The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: the effect of granisetron. Br J Cancer 69 (5): 957-60, 1994.  [PUBMED Abstract]
   
   
4. Fernández-Marcos A, Martín M, Sanchez JJ, et al.: Acute and anticipatory emesis in breast cancer patients. Support Care Cancer 4 (5): 370-7, 1996.  [PUBMED Abstract]
   
   
5. Roscoe JA, Morrow GR, Hickok JT, et al.: Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 20 (2): 113-21, 2000.  [PUBMED Abstract]
   
   
6. Reesal RT, Bajramovic H, Mai F: Anticipatory nausea and vomiting: a form of chemotherapy phobia? Can J Psychiatry 35 (1): 80-2, 1990.  [PUBMED Abstract]
   
   
7. Stockhorst U, Klosterhalfen S, Steingruber HJ: Conditioned nausea and further side-effects in cancer chemotherapy: a review. Journal of Psychophysiology 12 (suppl 1): 14-33, 1998. 
   
   
8. Morrow GR, Rosenthal SN: Models, mechanisms and management of anticipatory nausea and emesis. Oncology 53 (Suppl 1): 4-7, 1996.  [PUBMED Abstract]
   
   
9. Montgomery GH, Bovbjerg DH: The development of anticipatory nausea in patients receiving adjuvant chemotherapy for breast cancer. Physiol Behav 61 (5): 737-41, 1997.  [PUBMED Abstract]
   
   
10. Bovbjerg DH, Redd WH, Jacobsen PB, et al.: An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med 54 (6): 623-37, 1992 Nov-Dec.  [PUBMED Abstract]
    
    
11. Morrow GR, Roscoe JA, Hickok JT: Nausea and vomiting. In: Holland JC, Breitbart W, Jacobsen PB, et al., eds.: Psycho-oncology. New York, NY: Oxford University Press, 1998, pp 476-484. 
    
    
12. Andrykowski MA, Redd WH, Hatfield AK: Development of anticipatory nausea: a prospective analysis. J Consult Clin Psychol 53 (4): 447-54, 1985.  [PUBMED Abstract]
    
    
13. Roscoe JA, Morrow GR, Hickok JT, et al.: Biobehavioral factors in chemotherapy-induced nausea and vomiting. Journal of the National Comprehensive Cancer Network 2 (5): 501-8, 2004. 
    
    
14. Kvale G, Psychol C, Hugdahl K: Cardiovascular conditioning and anticipatory nausea and vomiting in cancer patients. Behav Med 20 (2): 78-83, 1994 Summer.  [PUBMED Abstract]
    
    
15. Montgomery GH, Tomoyasu N, Bovbjerg DH, et al.: Patients' pretreatment expectations of chemotherapy-related nausea are an independent predictor of anticipatory nausea. Ann Behav Med 20 (2): 104-9, 1998 Spring.  [PUBMED Abstract]
    
    
16. Shelke AR, Roscoe JA, Morrow GR, et al.: Effect of a nausea expectancy manipulation on chemotherapy-induced nausea: a university of Rochester cancer center community clinical oncology program study. J Pain Symptom Manage 35 (4): 381-7, 2008.  [PUBMED Abstract]
    
    
17. Tomoyasu N, Bovbjerg DH, Jacobsen PB: Conditioned reactions to cancer chemotherapy: percent reinforcement predicts anticipatory nausea. Physiol Behav 59 (2): 273-6, 1996.  [PUBMED Abstract]
    
    
18. Chin SB, Kucuk O, Peterson R, et al.: Variables contributing to anticipatory nausea and vomiting in cancer chemotherapy. Am J Clin Oncol 15 (3): 262-7, 1992.  [PUBMED Abstract]
    
    
19. Carey MP, Burish TG: Etiology and treatment of the psychological side effects associated with cancer chemotherapy: a critical review and discussion. Psychol Bull 104 (3): 307-25, 1988.  [PUBMED Abstract]
    
    
20. Lyles JN, Burish TG, Krozely MG, et al.: Efficacy of relaxation training and guided imagery in reducing the aversiveness of cancer chemotherapy. J Consult Clin Psychol 50 (4): 509-24, 1982.  [PUBMED Abstract]
    
    
21. Redd WH, Andresen GV, Minagawa RY: Hypnotic control of anticipatory emesis in patients receiving cancer chemotherapy. J Consult Clin Psychol 50 (1): 14-9, 1982.  [PUBMED Abstract]
    
    
22. Morrow GR, Morrell C: Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 307 (24): 1476-80, 1982.  [PUBMED Abstract]
    
    
23. Burish TG, Shartner CD, Lyles JN: Effectiveness of multiple muscle-site EMG biofeedback and relaxation training in reducing the aversiveness of cancer chemotherapy. Biofeedback Self Regul 6 (4): 523-35, 1981.  [PUBMED Abstract]
    
    
24. Kolko DJ, Rickard-Figueroa JL: Effects of video games on the adverse corollaries of chemotherapy in pediatric oncology patients: a single-case analysis. J Consult Clin Psychol 53 (2): 223-8, 1985.  [PUBMED Abstract]
    
    
25. Vasterling J, Jenkins RA, Tope DM, et al.: Cognitive distraction and relaxation training for the control of side effects due to cancer chemotherapy. J Behav Med 16 (1): 65-80, 1993.  [PUBMED Abstract]
    
    
26. Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.  [PUBMED Abstract]
    
    

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Acute/Delayed Emesis Etiology

Acute Emesis

• Incidence
  • The incidence of acute and delayed nausea and emesis was investigated in highly and moderately emetogenic chemotherapy treatment regimens. Patients were recruited from 14 oncology practices in 6 countries. Overall, more than 35% of patients experienced acute nausea and 13% experienced acute emesis. In patients receiving highly emetogenic chemotherapy, 60% experienced delayed nausea and 50% experienced delayed emesis. In those receiving moderately emetogenic chemotherapy, 52% experienced delayed nausea and 28% experienced delayed emesis.[1] Chemotherapy-induced nausea and vomiting (CINV) was a substantial problem for patients receiving moderately emetogenic chemotherapy in ten community oncology clinics.[2] Thirty-six percent of patients developed acute CINV, and 59% developed delayed CINV.



• Etiologies:
  • Chemotherapy is the most common treatment-related cause of nausea and vomiting. The incidence and severity of acute emesis in persons receiving chemotherapy varies according to many factors, including the particular drug, dose, schedule of administration, route, and individual patient variables. In the vast majority of cancer patients, these symptoms can be prevented or controlled.



• Risk factors for acute emesis include:[3]
  • Poor control with prior chemotherapy.
  • Female gender.
  • Younger age.



• Emetic classifications. The American Society of Clinical Oncology (ASCO) has developed a rating system for chemotherapeutic agents and their respective risk of acute and delayed emesis.[3]
  • High risk: Emesis that has been documented to occur in more than 90% of patients:
    • cisplatin (Platinol)
    • mechlorethamine (Mustargen)
    • streptozotocin (Zanosar)
    • cyclophosphamide (Cytoxan), 1,500 mg/m² or more
    • carmustine (BiCNU)
    • dacarbazine (DTIC-Dome)
    • dactinomycin
  
  
  
  • Moderate risk: Emesis that has been documented to occur in 30% to 90% of patients:
    • carboplatin (Paraplatin)
    • cyclophosphamide (Cytoxan), less than 1,500 mg/m²
    • daunorubicin (DaunoXome)
    • doxorubicin (Adriamycin)
    • epirubicin (Pharmorubicin)
    • idarubicin (Idamycin)
    • oxaliplatin (Eloxatin)
    • cytarabine (Cytosar), more than 1 g/m²
    • ifosfamide (Ifex)
    • irinotecan (Camptosar)
  
  
  
  • Low risk: Emesis that has been documented to occur in 10% to 30% of patients:
    • mitoxantrone (Novantrone)
    • paclitaxel (Taxol)
    • docetaxel (Taxotere)
    • mitomycin (Mutamycin)
    • topotecan (Hycamtin)
    • gemcitabine (Gemzar)
    • etoposide (Vepesid)
    • pemetrexed (Alimta)
    • methotrexate (Rheumatrex)
    • cytarabine (Cytosar), less than 1,000 mg/m²
    • fluorouracil (Efudex)
    • bortezomib (Velcade)
    • cetuximab (Erbitux)
    • trastuzumab (Herceptin)
  
  
  
  • Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:
    • vinorelbine (Navelbine)
    • bevacizumab (Avastin)
    • rituximab (Rituxan)
    • bleomycin (Blenoxane)
    • vinblastine (Velban)
    • vincristine (Oncovin)
    • busulphan (Myleran)
    • fludarabine (Fludara)
    • 2-chlorodeoxyadenosine (Leustatin)
  
  
  

In addition to emetogenic potential, the dose and schedule used are also extremely important factors. For example, a drug with a low emetogenic potential given in high doses may cause a dramatic increase in the potential to induce nausea and vomiting. Standard doses of cytarabine rarely produce nausea and vomiting, but these are often seen with high doses of this drug. Another factor to consider is the use of drug combinations. Because most patients receive combination chemotherapy, the emetogenic potential of all of the drugs combined and individual drug doses needs to be considered.

Delayed (or late) nausea and vomiting (emesis): Nausea and vomiting that occurs more than 24 hours after chemotherapy administration is considered delayed or late nausea and vomiting. Delayed nausea and vomiting is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more consecutive days.

• Etiologies:
  • Patients who experience acute emesis with chemotherapy are significantly more likely to have delayed emesis.



• Risk factors:
  • All predicative characteristics for acute emesis should be considered risk factors for delayed emesis.



• Emetic classifications:
  • See Acute Emesis section above.

References

1. Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.  [PUBMED Abstract]
   
   
2. Cohen L, de Moor CA, Eisenberg P, et al.: Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer 15 (5): 497-503, 2007.  [PUBMED Abstract]
   
   
3. Kris MG, Hesketh PJ, Somerfield MR, et al.: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24 (18): 2932-47, 2006.  [PUBMED Abstract]
   
   

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Prevention of Acute/Delayed Emesis

Antiemetic agents are the most common intervention in the management of treatment-related nausea and vomiting. The basis for antiemetic therapy is the neurochemical control of vomiting. Although the exact mechanism is not well understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, histamine (H1 and H2), dopamine, acetylcholine, opioids, and numerous other endogenous neurotransmitters.[1,2] Many antiemetics act by competitively blocking receptors for these substances, thereby inhibiting stimulation of peripheral nerves at the CTZ, and perhaps at the vomiting center. Most drugs with proven antiemetic activity can be categorized into one of the following groups:

• Competitive antagonists at dopaminergic (D2 subtype) receptors:
  • Phenothiazines.
  • Substituted benzamides.
  • Butyrophenones.
• Competitive antagonists at serotonergic (5-hydroxytryptamine-3 or 5-HT₃ subtype) receptors.
• Substance P antagonists (NK-1 receptor antagonists).
• Corticosteroids.
• Cannabinoids.
• Benzodiazepines.
• Olanzapine.

Although all routes of administration are listed for each of the following drugs, the intramuscular (IM) route should be used only when no other access is available. Intramuscular delivery is painful, is associated with erratic absorption of drug, and may lead to sterile abscess formation or fibrosis of the tissues. This is particularly important when more than 1 or 2 doses of a drug are to be given.

Phenothiazines act on dopaminergic receptors at the CTZ, and perhaps at other central nervous system (CNS) centers, and peripherally. With the exception of thioridazine, many phenothiazines possess antiemetic activity, including chlorpromazine given in the 10- to 50-mg dose range orally, IM, intravenously (IV), and rectally (pediatric dose for older than 12 years: 10 mg every 6–8 hours; for younger than 12 years: 5 mg every 6–8 hours); thiethylperazine given in the 5- to 10-mg dose range orally, IM, and IV; and perphenazine. The primary consideration in selecting among phenothiazines are differences in their adverse effect profiles, which substantially correlate with their structural classes. Generally, aliphatic phenothiazines (e.g., chlorpromazine, methotrimeprazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine, thiethylperazine, perphenazine, and fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions (EPRs).

This drug is perhaps the most frequently (and empirically) used antiemetic and, in low doses, is generally effective in preventing nausea associated with radiation therapy and in treating nausea and vomiting attributed to very low to moderately emetogenic chemotherapeutic drugs. It is a phenothiazine and can be given orally, IM, IV, and rectally. It is usually given in the 10- to 50-mg dose range (pediatric dose for children who weigh more than 10 kg or who are older than 2 years: orally or rectally, 0.4 mg/kg/d tid–qid; or IM, 0.1–0.15 mg/kg/dose tid–qid, maximum 40 mg/d). Higher prochlorperazine doses (e.g., 0.2–0.6 mg/kg/dose) are also used IV for chemotherapy with high emetogenic potential.[3,4] Phenothiazines may be of particular value in treating patients who experience delayed nausea and vomiting (postacute phase symptoms) on cisplatin regimens.[5]

As with other dopaminergic antagonists, the most common side effects of prochlorperazine are EPRs (acute dystonias, akathisias, neuroleptic malignant syndrome [uncommon], and rarely, akinesias and dyskinesias), and sedation. Marked hypotension may also result if IV prochlorperazine is administered rapidly at high doses. Administration over at least 30 minutes appears adequate to prevent hypotensive episodes.[6-8]

These two drugs represent another class of dopaminergic (D2 subtype) receptor antagonists that are structurally and pharmacologically similar to the phenothiazines. While droperidol is used primarily as an adjunct to anesthesia induction, haloperidol is indicated as a neuroleptic antipsychotic drug; however, both agents have potent antiemetic activity. Droperidol is administered IM or IV, typically from 1 to 2.5 mg every 2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[9,10] Haloperidol is administered IM, IV, or orally, typically from 1 to 4 mg every 2 to 6 hours.[11] Both agents may produce EPRs, akathisia, hypotension, and sedation.

Metoclopramide is a substituted benzamide, which, prior to the introduction of serotonin (5-HT₃) receptor antagonists, was considered the most effective single antiemetic agent against highly emetogenic chemotherapy such as cisplatin. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given IV at high doses (e.g., 0.5–3 mg/kg/dose), probably because it is a weak competitive antagonist (relative to other serotonin antagonists) at 5-HT₃ receptors. It may act on the CTZ and the periphery. Metoclopramide also increases lower esophageal sphincter pressure and enhances the rate of gastric emptying, which may factor into its overall antiemetic effect. It can be administered IV at the U.S. Food and Drug Administration (FDA)–approved dose of 1 to 2 mg/kg every 2 hours (or less frequently) for 3 to 5 doses. Metoclopramide has also been safely given by IV bolus injection at higher single doses (up to 6 mg/kg) and by continuous IV infusion, with or without a loading bolus dose, with efficacy comparable to multiple intermittent dosing schedules.[12-14] Metoclopramide is associated with akathisia and dystonic extrapyramidal effects, with the latter seen more commonly in persons younger than 30 years, and the former seen more frequently in patients older than 30 years. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize EPRs.[6,15] While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia, the subjective sense of restlessness or inability to sit still, is best treated by (1) switching to a lower potency neuroleptic for emesis, if possible; (2) lowering the dose; or (3) adding a benzodiazepine (i.e., lorazepam) or beta blocker (i.e., propranolol).

Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron, and palonosetron—are available in the United States. Tropisetron, while not approved by the FDA, is available internationally. Agents in this class are thought to prevent nausea and vomiting by preventing serotonin, which is released from enterochromaffin cells in the gastrointestinal (GI) mucosa, from initiating afferent transmission to the CNS via vagal and spinal sympathetic nerves.[16] The 5-HT₃ antagonists may also block serotonin stimulation at the CTZ and other CNS structures.

Several studies have demonstrated that ondansetron produces an antiemetic response that equals or is superior to high doses of metoclopramide, but ondansetron has a superior toxicity profile compared with dopaminergic antagonist agents.[17-23] Ondansetron (0.15 mg/kg) is given IV 15 to 30 minutes prior to chemotherapy and is repeated every 4 hours for two additional doses. Alternatively, for patients older than 18 years of age, a large multicenter study determined that a single 32-mg dose of ondansetron is more effective in treating cisplatin-induced nausea and vomiting than a single 8 mg dose, and is as effective as the standard regimen of three doses at 0.15 mg/kg given every 4 hours starting 30 minutes before chemotherapy.[24]

Currently, the oral and injectable ondansetron formulations are approved for use without dosage modification in patients older than 4 years, including the elderly and patients with renal insufficiency. Oral ondansetron is given 3 times daily starting 30 minutes before chemotherapy and continuing for up to 2 days after chemotherapy is completed. Patients older than 12 years should receive 4 mg per dose. Ondansetron is not approved for use in children younger than 4 years. Ondansetron clearance is diminished in patients with severe hepatic insufficiency; therefore, such patients should receive a single injectable or oral dose no greater than 8 mg. There is currently no information available evaluating the safety of repeated daily ondansetron doses in patients with hepatic insufficiency.

Other effective dosing schedules, such as a continuous IV infusion (e.g., 1 mg/hr for 24 hours) or oral administration have also been evaluated.[24] The major adverse effects include headache (which can be treated with mild analgesics), constipation or diarrhea, fatigue, dry mouth, and transient asymptomatic elevations in liver function tests (alanine [ALT] and aspartate [AST] transaminases), which may be related to concurrent cisplatin administration.[25] Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events.[26] In addition, a few case reports have implicated ondansetron in causing EPRs. However, it is not clear in some cases whether the events described were in fact EPRs, and in other reports the evidence is confounded by concurrent use of other agents that are known to produce EPRs. Nevertheless, the greatest advantage of serotonin receptor antagonists over dopaminergic receptor antagonists is that they have fewer adverse effects. Despite prophylaxis with ondansetron, many patients receiving doxorubicin, cisplatin, or carboplatin will experience acute and delayed-phase nausea and vomiting.[27] A randomized, double-blind, placebo-controlled trial suggests that the addition of aprepitant, a neurokinin-1 (NK1) antagonist, may mitigate nausea and vomiting.[28] The optimal dose of aprepitant may be 125 mg on day 1 followed by 80 mg on days 2 to 5.[29]

Granisetron has demonstrated efficacy in preventing and controlling nausea and vomiting at a broad range of doses (e.g., 10–80 µg/kg and empirically, 3 mg per dose). In the United States, granisetron injection and oral tablets are approved for initial and repeat prophylaxis for patients receiving emetogenic chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically and pharmacokinetically distinct from ondansetron; however, clinically it appears equally efficacious and equally safe.[30-32] Both granisetron formulations are given before chemotherapy, as either a single IV dose of 10 µg/kg (0.01 mg/kg) or 1 mg orally every 12 hours.

Both granisetron formulations and ondansetron injection share the same indication against highly emetogenic chemotherapy. In contrast, the oral ondansetron formulation has been approved only for use against nausea and vomiting associated with moderately emetogenic chemotherapy.

Currently, granisetron injection is approved for use without dosage modification in patients older than 2 years, including the elderly and patients with hepatic and renal insufficiency. Oral granisetron has not yet been approved for use in pediatric patients.

Both oral and injection formulations are indicated for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy including initial and repeat courses. Oral dolasetron should be dosed as 100 mg within 1 hour before chemotherapy. Dolasetron should be given IV or orally at 1.8 mg/kg as a single dose approximately 30 minutes before chemotherapy.

The effectiveness of oral dolasetron in the prevention of chemotherapy-induced nausea and vomiting has been proven in a large randomized, double-blind, comparative trial of 399 patients.[33] Oral dolasetron was administered in the range of 25 to 200 mg 1 hour prior to chemotherapy. The other study arm consisted of oral ondansetron (8 mg) administered 1.5 hours before chemotherapy and every 8 hours after, for a total of 3 doses. Complete response (CR) rates improved with increasing doses of dolasetron. Both dolasetron 200 mg and ondansetron had significantly higher CR rates as compared with dolasetron 25 mg or 50 mg. (CR was defined as no emetic episodes and no use of escape antiemetic medications.) Dolasetron injection has also been proven effective in the prevention of chemotherapy-induced nausea and vomiting.[34]

Palonosetron is a new 5-HT₃ receptor antagonist (second generation) that has antiemetic activity at both central and gastrointestinal sites. In comparison to the older 5-HT₃ receptor antagonists, it has a higher binding affinity to the 5-HT₃ receptors, a higher potency, a significantly longer half-life (approximately 40 hours, four to five times longer than that of dolasetron, granisetron, or ondansetron), and an excellent safety profile.[35] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[35] In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and the delayed period for patients who received 0.25 mg of palonosetron alone compared with either ondansetron or dolasetron alone.[36,37] Dexamethasone was not given with the 5-HT₃ receptor antagonists in these studies, and it is not yet known whether the differences in CR would persist if dexamethasone was used. In another study,[38] 650 patients receiving highly emetogenic chemotherapy (cisplatin ≥60 mg/m²) also received either dexamethasone and one of two doses of palonosetron (0.25 mg or 0.75 mg) or dexamethasone and ondansetron (32 mg). Single-dose palonosetron was as effective as ondansetron in preventing acute chemotherapy-induced nausea and vomiting with dexamethasone pretreatment; it was significantly more effective than ondansetron throughout the 5-day postchemotherapy period. In an analysis of the patients in the above studies who received repeated cycles of chemotherapy, one author [39] reported that the CR rates for both acute and delayed chemotherapy-induced nausea and vomiting were maintained with single IV doses of palonosetron without concomitant corticosteroids. These data have been presented in abstract form only and will require further review. Based on the above studies, palonosetron was approved by the FDA in July 2003 for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy; and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Clinicians should note that studies suggest that there are no major differences in efficacy or toxicity of the three first-generation 5-HT₃ receptor antagonists (dolasetron, granisetron, ondansetron) in the treatment of chemotherapy-induced acute nausea and vomiting. These three agents are equivalent in efficacy and toxicity when used in appropriate doses.[40-43] Although these agents have been shown to be effective in the first 24 hours postchemotherapy (acute phase), they have not been demonstrated to be effective in days 2 to 5 postchemotherapy (delayed phase).[44,45,27]

Palonosetron, the second-generation 5-HT₃ receptor antagonist, has been approved for the control of delayed emesis for patients receiving moderately emetogenic chemotherapy.[36,37]

Despite the use of both first-generation and second-generation 5-HT₃ receptor antagonists, the control of acute chemotherapy-induced nausea and vomiting, and especially delayed nausea and vomiting, is suboptimal and there is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.[44,45,27,46]

The initial clinical studies using the NK-1 receptor antagonists [47-50] demonstrated that the addition of an NK-1 receptor antagonist (CP-122,721, CJ-11,794, MK-0869 [aprepitant]) to a 5-HT₃ receptor antagonist plus dexamethasone prior to cisplatin chemotherapy improved the control of acute emesis compared to 5-HT₃ plus dexamethasone, and improved the control of delayed emesis compared with placebo. In addition, as a single agent, MK-0869 (aprepitant) had a similar effect on cisplatin-induced acute emesis as ondansetron but was superior in the control of delayed emesis. Subsequent studies [51,52] showed that the combination of aprepitant and dexamethasone was similar to a 5-HT₃ receptor antagonist plus dexamethasone in controlling acute emesis but was inferior in controlling acute emesis compared with triple therapy (aprepitant, 5-HT₃ receptor antagonist, and dexamethasone). These studies also confirmed the improvement of delayed emesis with the use of aprepitant compared with placebo. Two studies [29,53] have also shown an improvement in cisplatin-induced delayed emesis with the combination of aprepitant and dexamethasone compared with dexamethasone alone, with the improvement maintained over repeat cycles of cisplatin chemotherapy.

In two randomized, double-blind, parallel, multicenter, controlled studies (520 patients in each study), patients received cisplatin (≥70 mg/m²) and were randomized to receive either standard therapy of a 5-HT₃ receptor antagonist (ondansetron) and dexamethasone prechemotherapy and dexamethasone postchemotherapy (days 2–4) or standard therapy plus aprepitant prechemotherapy and on days 2 and 3 postchemotherapy.[54,28] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute period (83%–89%) and the delayed period (68%–75%), compared with the CR of the standard therapy group in the acute period (68%–78%) and delayed period (47%–56%). Nausea was improved in the aprepitant group for some, but not all of the various specific measures of nausea.[28] The studies discussed above formed the basis for the approval of aprepitant by the FDA in March 2003. In combination with other antiemetics, aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[55]

All of the initial studies using aprepitant have been conducted in patients receiving highly emetogenic chemotherapy, such as cisplatin-based chemotherapy regimens. Subsequently, one group [56] presented a study on the use of aprepitant in 862 breast cancer patients receiving moderately emetogenic chemotherapy (i.e., cyclosphamide, doxorubicin). Two regimens were compared. Because the chemotherapy was moderately emetogenic, steroids were omitted from both arms, as illustrated by the following table.

There was a significant improvement in complete response (no emesis, no rescue) in the 24 hours after chemotherapy in the patients receiving aprepitant; however, there was no significant improvement in complete response on days 2 to 5 in the postchemotherapy period when aprepitant alone was compared with ondansetron alone. The overall (days 1–5) complete response was significantly improved for the aprepitant-containing regimen, most likely because of the improvement in the first 24 hours. The control of nausea in moderately emetogenic chemotherapy was not improved with the use of aprepitant without steroids on days 2 and 3 postchemotherapy. The role of aprepitant in moderately emetogenic chemotherapy remains unclear. These results were consistent for multiple cycles of chemotherapy.[57] One open-label study demonstrated that in the 5 days postchemotherapy, aprepitant in combination with palonosetron and dexamethasone is safe and highly effective in preventing chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy.[58]

Steroids are sometimes used as single agents against mild to moderately emetogenic chemotherapy, but are more often used in antiemetic drug combinations.[59-61] Their antiemetic mechanism of action is not fully understood, but they may affect prostaglandin activity in the brain. Clinically, steroids quantitatively decrease or eliminate episodes of nausea and vomiting and may improve patients’ mood, thus producing a subjective sense of well-being or euphoria (although they also can cause depression and anxiety). In combination with high-dose metoclopramide, steroids may mitigate adverse effects, such as the frequency of diarrheal episodes.

Steroids are often given IV before chemotherapy and may or may not be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice in treating nausea and vomiting in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally, IM, or IV in the dose range of 8 to 40 mg (pediatric dose: 0.25–0.5 mg/kg).[62-66] Methylprednisolone is also administered orally, IM, or IV at doses and schedules that vary from 40 to 500 mg every 6 to 12 hours for up to 20 doses.[61,67]

Dexamethasone is also used orally for delayed nausea and vomiting. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including immunosuppression, proximal muscle weakness (especially involving the thighs and upper arms), aseptic necrosis of the long bones, cataract formation, hyperglycemia and exacerbation of preexisting diabetes or escalation of subclinical diabetes to clinical pathology, adrenal suppression with hypocortisolism, lethargy, weight gain, GI irritation, insomnia, anxiety, mood changes, and psychosis. A study that examined chemotherapy in a group of patients with ovarian cancer found that short-term use of glucocorticoids as antiemetics had no negative effects on outcomes (i.e., overall survival, efficacy of chemotherapy).[68] As had previously been shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT₃ blocking agents.[69-73] If given IV, dexamethasone should be given over 10 to 15 minutes, since rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[65,74-76]

Prednisone and adrenocorticotropic hormone (ACTH) given concomitantly with other active antiemetic agents have also demonstrated efficacy against cisplatin-containing chemotherapy during the acute phase (within 24 hours after receiving chemotherapy).[77-79] In a double-blind randomized study of metoclopramide and dexamethasone with or without 1 mg of ACTH, patients receiving ACTH prophylaxis for cisplatin-containing chemotherapy experienced a significantly decreased incidence and severity of delayed emesis for up to 72 hours after treatment.[79]

Cannabinoids presumably target higher CNS structures to prevent nausea and vomiting.[80] Dronabinol (delta-9-tetrahydrocannabinol) is one of the psychoactive substances present in crude marijuana. Because of cultural and societal constraints and a low therapeutic index at clinically useful dosages, cannabinoids are often not among agents that are first selected for clinical use, but may be accepted and useful in selected patients.[81] Dronabinol is administered orally at 5 to 15 mg/m², 1 to 3 hours before chemotherapy, then every 2 to 4 hours for up to 6 doses/day.[82-84]

Adverse effects experienced along with the pharmacologic and psychogenic effects of cannabinoids include the following:

• Acute withdrawal syndrome.
• Sedation.
• Dry mouth.
• Orthostatic hypotension.
• Dizziness.
• Ataxia.

Dronabinol produces the following effects on the CNS at minimally effective dosages:[85-88]

• Euphoria or dysphoria.
• Feelings of detachment, depression, anxiety, paranoia, and panic.
• Decreased cognitive function.
• Memory loss.
• Increased tendencies toward impulsive and compulsive behaviors.
• Altered perceptions such as a distorted sense of time.
• Other sensory distortions.
• Hallucinations.
• Psychotic organic brain syndrome (rarely).

Cardiovascular adverse effects typically manifest at dosages somewhat greater than those recommended for antiemetic effect and include tachycardia, vasodilation with variable effects on blood pressure, orthostatic symptoms, and decreased body temperature. With chronic administration, tolerance to cardiovascular and subjective effects may occur within days to weeks after treatment onset.[80]

Benzodiazepines such as lorazepam, midazolam, and alprazolam, have become recognized as valuable adjuncts in the prevention and treatment of anxiety and anticipatory nausea and vomiting symptoms associated with chemotherapy, especially with the highly emetogenic regimens given to children.[89-91] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents. Therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents.[92] Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, they markedly decrease the severity of EPRs, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.

Lorazepam may be administered orally, IM, IV, and sublingually. Dosages range from 0.5 to 3 mg (alternatively, 0.025–0.05 mg/kg, or 1.5 mg/m², but ≤4 mg per dose) in adults and 0.03 to 0.05 mg/kg in children every 6 to 12 hours.[89,93-95] Midazolam produces mild-to-marked sedation for 1 to 4.5 hours at doses equal to 0.04 mg/kg given IV over 3 to 5 minutes.[96,97] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.[98]

The adverse effects of benzodiazepine include sedation, perceptual disturbances, disorders of micturition and/or defecation, visual disturbances, hypotension, anterograde amnesia, psychological dependence, confusion, ataxia, and depressed mental acuity with intoxication.[99]

Olanzapine is an antipsychotic in the thienobenzodiazepine drug class that blocks multiple neurotransmitters: dopamine at D₁, D₂, D₃, and D₄ brain receptors; serotonin at 5-HT_2a, 5-HT_2c, 5-HT₃, and 5-HT₆ receptors; catecholamines at alpha-1 adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H₁ receptors.[100] Common side effects are sedation and weight gain,[101,102] as well as an association with the onset of diabetes mellitus.[103] Olanzapine's activity at multiple receptors, particularly at the D₂ and 5-HT₃ receptors that appear to be involved in nausea and emesis, suggests that it may have significant antiemetic properties.

There have been case reports on the use of olanzapine as an antiemetic.[104-108] These case reports prompted a phase I study in which olanzapine was used for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.[109] The protocol was completed by 15 patients, and no grade 4 toxicities were seen. The maximum tolerated dose was 5 mg per day for 2 days prior to chemotherapy and 10 mg per day for 7 days postchemotherapy. Based on these data, olanzapine appeared to be a safe and effective agent for the prevention of delayed emesis in chemotherapy-naive cancer patients receiving cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.

Using the maximum tolerated dose of olanzapine in the phase I trial, a phase II trial was performed for the prevention of chemotherapy-induced nausea and vomiting in patients receiving their first course of either highly emetogenic or moderately emetogenic chemotherapy. Olanzapine was added to granisetron and dexamethasone prechemotherapy and to dexamethasone postchemotherapy. CR (no emesis, no rescue) was 100% for the acute period (24 hours postchemotherapy), 80% for the delayed period (days 2–5 postchemotherapy), and 80% for the overall period (0–120 hours postchemotherapy) in ten patients receiving highly emetogenic chemotherapy (cisplatin, ≥70 mg/m²). CR was also 100% for the acute period, 85% for the delayed period, and 85% for the overall period in 20 patients receiving moderately emetogenic chemotherapy (doxorubicin, ≥50 mg/m²). Nausea was very well controlled in the patients receiving highly emetogenic chemotherapy, with no patient having nausea (0 on a scale of 0–10, M. D. Anderson Symptom Inventory [MDASI]) in the acute or delayed periods. Nausea was also well controlled in patients receiving moderately emetogenic chemotherapy, with no nausea in 85% of patients in the acute period and in 65% in the delayed and overall periods. There were no grade 3 or 4 toxicities. Based on these data, olanzapine appeared to be safe (sedation was the only dose-limiting toxicity) and effective in controlling acute and delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic and moderately emetogenic chemotherapy.[110]

Current guidelines [111,112] recommend that prechemotherapy management of chemotherapy-induced nausea and vomiting (CINV) be based on the emetogenic potential of the chemotherapy agent(s) selected. For patients receiving regimens with high emetogenic potential, the combination of a 5-HT₃ receptor antagonist, aprepitant, and dexamethasone is recommended prechemotherapy; lorazepam may also be used. Aprepitant and dexamethasone are recommended postchemotherapy for the prevention of delayed emesis.

For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT₃ receptor antagonist and dexamethasone should be used prechemotherapy, with or without lorazepam. Patients receiving the combination of an anthracycline and cyclophosphamide and select patients receiving certain other agents of moderate emetic risk, such as cisplatin (<50 mg/m²) or doxorubicin, should also receive aprepitant. Postchemotherapy, a 5-HT₃ receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.

For regimens with low emetogenic potential, dexamethasone is recommended with or without lorazepam. For regimens with minimal emetogenic risk, no prophylaxis is suggested.[111,112]

Antiemetic guidelines [111,112] have included the available oral 5-HT₃ receptor antagonists as optional therapy for the prevention of delayed emesis, but the level of evidence supporting this practice is low.[44]

Clinicians and other health care professionals who are involved in administering chemotherapy should be aware that studies have strongly suggested that patients experience more acute and delayed chemotherapy-induced nausea and vomiting than is perceived by practitioners.[113,44,114] In addition, the current and new agents have been used as prophylaxis for acute and delayed chemotherapy-induced nausea and vomiting and have not been studied for use in established chemotherapy-induced nausea and vomiting.[44,45] One study reported the effective use of intravenous palonosetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy.[115]

Pre- and postchemotherapy recommendations by emetogenic potential are summarized in the table on Antiemetic Recommendations by Emetic-Risk Categories.