Treatment-Related Nausea and Vomiting (PDQ®) 1/2 –Health Professional Version - National Cancer Institute

Treatment-Related Nausea and Vomiting (PDQ®)–Health Professional Version - National Cancer Institute

Treatment-Related Nausea and Vomiting (PDQ®)–Health Professional Version

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ON THIS PAGE

• Overview
• Pathophysiology
• General Risk Factors and Etiologies
• Anticipatory Nausea and Vomiting
• Acute or Delayed Chemotherapy-Induced Nausea and Vomiting Etiology
• Prevention and Management of Acute or Delayed Nausea and Vomiting
• Nonpharmacologic Management of Nausea and Vomiting
• Radiation-Induced Nausea and Vomiting
• Pediatric Chemotherapy-Induced Acute Nausea and Vomiting
• Pediatric Delayed Nausea and Vomiting
• Pediatric Anticipatory Nausea and Vomiting
• Changes to This Summary (10/30/2019)
• About This PDQ Summary

Overview

Prevention and control of nausea and vomiting (emesis) (N&V) are paramount in the treatment of cancer patients. Chemotherapy-induced N&V is one of the most distressing acute side effects of cancer treatment; it occurs in up to 80% of patients and can have a significant impact on a patient’s quality of life. N&V can also result in the following:

• Serious metabolic derangements.
• Nutritional depletion and anorexia.
• Deterioration of the patient’s physical and mental status.
• Esophageal tears.
• Fractures.
• Wound dehiscence.
• Withdrawal from potentially useful and curative antineoplastic treatment.
• Degeneration of self-care and functional ability.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

Pathophysiology

Nausea is the subjective phenomenon of an unpleasant, wavelike sensation experienced in the back of the throat and/or the epigastrium that may culminate in vomiting (emesis). Vomiting is the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. Retching involves the gastric and esophageal movements of vomiting without expulsion of vomitus; it is also referred to as dry heaves.

Progress has been made in understanding the neurophysiologic mechanisms that control nausea and vomiting (N&V). 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 includes a convergence of afferent stimulation from the following:[1,2]

• A chemoreceptor trigger zone (CTZ, area postrema).
• The cerebral cortex and the limbic system in response to sensory stimulation (particularly smell and taste), psychological 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.

Neurotransmitters (including serotonin, substance P, and dopamine) found in the CTZ, the vomiting center (thought to be located in the nucleus tractus solitarius), and enterochromaffin cells in the gastrointestinal tract then release efferent impulses that are transmitted to the abdominal musculature, salivation center, and respiratory center. The relative contribution from these multiple pathways culminating in N&V symptoms is complex and is postulated to account for the variable emetogenicity (intrinsic emetogenicity and mitigating factors [i.e., dosage, administration route, and exposure duration]) and emetogenic profile (i.e., time to onset, symptom severity, and duration) of agents.[3,4]

References

1. Wickham R: Evolving treatment paradigms for chemotherapy-induced nausea and vomiting. Cancer Control 19 (2 Suppl): 3-9, 2012. [PUBMED Abstract]
2. Navari RM: Antiemetic control: toward a new standard of care for emetogenic chemotherapy. Expert Opin Pharmacother 10 (4): 629-44, 2009. [PUBMED Abstract]
3. Cefalo MG, Ruggiero A, Maurizi P, et al.: Pharmacological management of chemotherapy-induced nausea and vomiting in children with cancer. J Chemother 21 (6): 605-10, 2009. [PUBMED Abstract]
4. Darmani NA, Crim JL, Janoyan JJ, et al.: A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: evidence from the least shrew. Brain Res 1248: 40-58, 2009. [PUBMED Abstract]

General Risk Factors and Etiologies

In This Section

• Classifications

Although most patients receiving chemotherapy are at risk of nausea and vomiting (emesis) (N&V), the onset, severity, triggers, and duration vary. Factors related to the tumor, treatment, and patient all contribute to N&V, including tumor location, chemotherapy agents used, and radiation exposure.[1-3]

Patient-related factors may include the following:

• Incidence and severity of N&V during past courses of chemotherapy. Patients with poor control of N&V during past chemotherapy cycles are likely to experience N&V in subsequent cycles.
• History of chronic alcohol use. Patients with a history of chronic high intake of alcohol are less likely to experience cisplatin-induced N&V.[4]
• Age. N&V is more likely to occur in patients younger than 50 years.[5]
• Gender. N&V is more likely to occur in women.[5,6]
• History of morning sickness or emesis during pregnancy.

Additional causal factors may include the following:

• Fluid and electrolyte imbalances such as hypercalcemia, volume depletion, or water intoxication.
• Tumor invasion or growth in the gastrointestinal tract, liver, or central nervous system, especially the posterior fossa.
• Constipation.
• Certain drugs such as opioids.
• Infection or septicemia.
• Uremia.

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 Adverse effects section in the Opioids section of the PDQ summary on Cancer Pain for more information about opioid-induced N&V.)

Classifications

N&V has been classified as acute, delayed, anticipatory, breakthrough, refractory, and chronic, as outlined below:[7-9]

• Acute N&V: N&V experienced during the first 24 hours after chemotherapy administration is considered acute N&V.[10]
• Delayed (or late) N&V: 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 N&V (ANV): ANV is nausea and/or vomiting that occurs before a new cycle of chemotherapy is begun, 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 chemotherapy treatments after which the patient experienced acute or delayed N&V.
• Breakthrough N&V: Vomiting that occurs within 5 days of prophylactic use of antiemetics and requires rescue is termed breakthrough N&V.
• Refractory N&V: N&V that does not respond to treatment.
• Chronic N&V in advanced-cancer patients: Chronic N&V in patients with advanced cancer is N&V associated with a variety of potential etiologies. A definitive understanding of cause is neither well known nor well researched, but potential causal factors include gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic chemotherapy–induced, and radiation-induced mechanisms.[11]

The National Cancer Institute has published a descriptive terminology that can be used for adverse event reporting (refer to Table 1). A grading (severity) scale is provided for each term.

Table 1. National Cancer Institute’s Common Terminology Criteria for Adverse Events: N&Va

Adverse Event	Grade	Description
IV = intravenous; N&V = nausea and vomiting (emesis); TPN = total parenteral nutrition.
aAdapted from National Cancer Institute.[12]
bDefinition: A disorder characterized by a queasy sensation and/or the urge to vomit.
cDefinition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth.
Nauseab	1	Loss of appetite without alteration in eating habits
	2	Oral intake decreased without significant weight loss, dehydration, or malnutrition
	3	Inadequate oral caloric or fluid intake; tube feeding, TPN, or hospitalization indicated
	4	Grade not assigned
	5	Grade not assigned
Vomitingc	1	Intervention not indicated
	2	Outpatient IV hydration; medical intervention indicated
	3	Tube feeding, TPN, or hospitalization indicated
	4	Life-threatening consequences; urgent intervention indicated
	5	Death

References

1. Farrell C, Brearley SG, Pilling M, et al.: The impact of chemotherapy-related nausea on patients' nutritional status, psychological distress and quality of life. Support Care Cancer 21 (1): 59-66, 2013. [PUBMED Abstract]
2. Dranitsaris G, Bouganim N, Milano C, et al.: Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11 (1): 14-21, 2013. [PUBMED Abstract]
3. Bouganim N, Dranitsaris G, Hopkins S, et al.: Prospective validation of risk prediction indexes for acute and delayed chemotherapy-induced nausea and vomiting. Curr Oncol 19 (6): e414-21, 2012. [PUBMED Abstract]
4. 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]
5. Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: a review. Ann Oncol 2 (2): 107-14, 1991. [PUBMED Abstract]
6. 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]
7. Kris MG, Urba SG, Schwartzberg LS: Clinical roundtable monograph. Treatment of chemotherapy-induced nausea and vomiting: a post-MASCC 2010 discussion. Clin Adv Hematol Oncol 9 (1): suppl 1-15, 2011. [PUBMED Abstract]
8. Hesketh PJ: Chemotherapy-induced nausea and vomiting. N Engl J Med 358 (23): 2482-94, 2008. [PUBMED Abstract]
9. Grunberg SM, Osoba D, Hesketh PJ, et al.: Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--an update. Support Care Cancer 13 (2): 80-4, 2005. [PUBMED Abstract]
10. 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.
11. 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]
12. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. Bethesda, Md: U.S. Department of Health and Human Services, National Institutes of Health, 2017. Available online. Last accessed October 27, 2019.

Anticipatory Nausea and Vomiting

In This Section

• Prevalence
• Classical Conditioning
• Variables Correlated with ANV
• Treatment of ANV

Prevalence

The prevalence of anticipatory nausea and vomiting (ANV) has varied, owing to changing definitions and assessment methods.[1] However, anticipatory nausea appears to occur in approximately 29% of patients receiving chemotherapy (about one of three patients), while anticipatory vomiting appears to occur in 11% of patients (about one of ten patients).[2] With the introduction of new pharmacologic agents such as 5-hydroxytryptamine-3 (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.

Classical Conditioning

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 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 (N&V) (in some patients). The drugs are paired with a variety of other neutral, environmental stimuli (e.g., smells of the setting, presence of the 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 is 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 before treatment with any chemotherapy is very rare, and few patients ever experience ANV without previous postchemotherapy nausea.[8] Also, most studies have found (1) a higher probability of ANV with increasing numbers of chemotherapy infusions, and (2) the intensity of ANV increasing 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]

Variables Correlated with ANV

Many variables have been investigated as potential risk factors that correlate with the incidence of ANV. There is 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 after the first chemotherapy infusion could identify patients at increased risk.[11]

Variables Found to Correlate With ANV

1. Age younger than 50 years.
2. N&V after the 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 the last chemotherapy session.
6. Susceptibility to motion sickness.
7. Female gender.
8. High-state anxiety (anxiety reactive to specific situations).[12,13]
9. Greater reactivity of the autonomic nervous system and slower reaction time.[14]
10. Patient expectations of chemotherapy-related nausea before beginning treatment.[15,16]
11. Percentage of infusions of chemotherapy followed by nausea.[17]
12. Postchemotherapy dizziness.
13. Longer latency of onset of posttreatment N&V.[18]
14. Emetogenic potential of various chemotherapeutic agents. Patients receiving drugs with a moderate to severe potential for posttreatment N&V are more likely to develop ANV.[12]
15. History of morning sickness during pregnancy.

Treatment of ANV

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 the following:

• Progressive muscle relaxation with guided imagery.[20]
• Hypnosis.[21]
• Systematic desensitization.[22]
• Electromyography and thermal biofeedback.[23]
• 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 should be considered as treatment. Referral to a psychologist or other mental health professional with specific training and experience in working with cancer patients should be considered when ANV is identified. The earlier ANV is identified, the more likely treatment will be effective; thus, early screening and referral are essential. However, physicians and nurses underestimate the incidence of chemotherapy-induced N&V.[26][Level of evidence: II]

Clearly, the most important aspect of ANV is prevention of acute and delayed N&V associated with chemotherapy. Most antiemetics have not shown benefit for the treatment of ANV, but the use of antiemetics during chemotherapy may have a dramatic effect in decreasing the incidence of ANV. The only class of medication that has shown benefit in some studies is benzodiazepines, most commonly lorazepam.[27][Level of evidence: IV]

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. J Natl Compr Canc Netw 2 (5): 501-8, 2004. [PUBMED Abstract]
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. Chan CW, Cheng KK, Lam LW, et al.: Psycho-educational intervention for chemotherapy-associated nausea and vomiting in paediatric oncology patients: a pilot study. Hong Kong Med J 14 (5 Suppl): 32-5, 2008. [PUBMED Abstract]
27. Rock EM, Limebeer CL, Parker LA: Anticipatory nausea in animal models: a review of potential novel therapeutic treatments. Exp Brain Res 232 (8): 2511-34, 2014. [PUBMED Abstract]

Acute or Delayed Chemotherapy-Induced Nausea and Vomiting Etiology

In This Section

• Acute Nausea and Vomiting (N&V)
• Delayed N&V

Acute Nausea and Vomiting (N&V)

The incidence of acute N&V with moderate- or high-risk chemotherapy ranges from 30% to 90%.[1-3] It can result in significant morbidity and can negatively affect quality of life. However, in recent years many new antiemetic medications and combinations have become available, dramatically decreasing the incidence and severity of this dreaded complication. Risk factors include the emetogenic potential of the specific drug, the dose used, the treatment schedule, and how chemotherapy agents are combined. For example, a drug with a low emetogenic potential given in high doses may cause a dramatic increase in the potential to induce N&V.[4] Standard doses of cytarabine rarely produce N&V, but N&V is often seen with high doses of this drug. Another influencing factor 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 need to be considered.[5-9]

Other risk factors include the following:[10]

• Poor control with previous chemotherapy.
• Female gender.
• Age younger than 50 years.
• Experience with previous chemotherapy.
• History of motion sickness.
• History of morning sickness during pregnancy.
• Dehydration.
• Malnutrition.
• Recent surgery.
• Radiation therapy.

The American Society of Clinical Oncology (ASCO) provides a summary of intravenous chemotherapeutic agents and their respective risk of acute and delayed emesis.[10]

• High risk: Emesis that has been documented to occur in more than 90% of patients:
  • Anthracycline/cyclophosphamide combination.
  • Carmustine.
  • Cisplatin.
  • Cyclophosphamide (≥1,500 mg/m2).
  • Dacarbazine.
  • Dactinomycin.
  • Mechlorethamine.
  • Streptozotocin.
• Moderate risk: Emesis that has been documented to occur in 30% to 90% of patients:
  • Alemtuzumab.
  • Azacitidine.
  • Bendamustine.
  • Carboplatin.
  • Clofarabine.
  • Cyclophosphamide (<1,500 mg/m2).
  • Cytarabine (>1,000 mg/m2).
  • Daunorubicin.
  • Doxorubicin.
  • Epirubicin.
  • Idarubicin.
  • Ifosfamide
  • Irinotecan.
  • Irinotecan liposomal injection.
  • Oxaliplatin.
  • Romidepsin.
  • Temozolomide.
  • Thiotepa.
  • Trabectedin.
• Low risk: Emesis that has been documented to occur in 10% to 30% of patients:
  • Aflibercept.
  • Atezolizumab.
  • Belinostat.
  • Blinatumomab.
  • Bortezomib.
  • Brentuximab.
  • Cabazitaxel.
  • Carfilzomib.
  • Cetuximab.
  • Cytarabine (<1,000 mg/m2).
  • Docetaxel.
  • Elotuzumab.
  • Eribulin.
  • Etoposide.
  • Fluorouracil.
  • Gemcitabine.
  • Ipilimumab.
  • Ixabepilone.
  • Methotrexate.
  • Mitomycin.
  • Mitoxantrone.
  • Nab-paclitaxel.
  • Necitumumab.
  • Paclitaxel.
  • Panitumumab.
  • Pegylated liposomal doxorubicin.
  • Pemetrexed.
  • Pertuzumab.
  • Temsirolimus.
  • Topotecan.
  • Trastuzumab-emtansine.
• Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:
  • Bevacizumab.
  • Bleomycin.
  • Busulfan.
  • Cladribine.
  • Daratumumab.
  • Fludarabine.
  • Nivolumab.
  • Obinutuzumab.
  • Ofatumumab.
  • Pembrolizumab.
  • Pralatrexate.
  • Ramucirumab.
  • Rituximab.
  • Trastuzumab.
  • Vinblastine.
  • Vincristine.
  • Vinorelbine.

ASCO provides a summary of oral chemotherapeutic agents and their respective risk of acute and delayed emesis.[10]

• High risk: Emesis that has been documented to occur in more than 90% of patients:
  • Altretamine.
  • Procarbazine.

• Moderate risk: Emesis that has been documented to occur in 30% to 90% of patients:
  • Bosutinib.
  • Cabozantinib.
  • Ceritinib.
  • Crizotinib.
  • Cyclophosphamide.
  • Imatinib.
  • Lenvatinib.
  • Temozolomide.
  • Trifluridine-tipiracil.
  • Vinorelbine.

• Low risk: Emesis that has been documented to occur in 10% to 30% of patients:
  • Afatinib.
  • Alectinib.
  • Axitinib.
  • Capecitabine.
  • Cobimetinib.
  • Dabrafenib.
  • Dasatinib.
  • Etoposide.
  • Everolimus.
  • Fludarabine.
  • Ibrutinib.
  • Idelalisib.
  • Ixazomib.
  • Lapatinib.
  • Lenalidomide.
  • Olaparib.
  • Osimertinib.
  • Nilotinib.
  • Palbociclib.
  • Panobinostat.
  • Pazopanib.
  • Ponatinib.
  • Regorafenib.
  • Sonidegib.
  • Sunitinib.
  • Thalidomide.
  • Trametinib.
  • Vandetanib.
  • Venetoclax.
  • Vorinostat.

• Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:
  • Chlorambucil.
  • Erlotinib.
  • Gefitinib.
  • Hydroxyurea.
  • Melphalan.
  • Methotrexate.
  • Pomalidomide.
  • Ruxolitinib.
  • Sorafenib.
  • Thioguanine.
  • Vemurafenib.
  • Vismodegib.

Delayed N&V

Delayed (or late) N&V occurs more than 24 hours after chemotherapy administration. Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or given on 2 or more consecutive days.[1,11,12]

• Etiologies:
  • Patients who experience acute emesis with chemotherapy are significantly more likely to have delayed emesis.
• Risk factors:
  • All predictive characteristics for acute emesis are considered risk factors for delayed emesis.
• Emetic classifications:
  • Refer to the Acute Nausea and Vomiting (N&V) section of this summary for more information.

References

1. Hesketh PJ, Sanz-Altamira P, Bushey J, et al.: Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. Support Care Cancer 20 (5): 1043-7, 2012. [PUBMED Abstract]
2. Schwartzberg L: Addressing the value of novel therapies in chemotherapy-induced nausea and vomiting. Expert Rev Pharmacoecon Outcomes Res 14 (6): 825-34, 2014. [PUBMED Abstract]
3. Sekine I, Segawa Y, Kubota K, et al.: Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer Sci 104 (6): 711-7, 2013. [PUBMED Abstract]
4. 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]
5. Viale PH, Grande C, Moore S: Efficacy and cost: avoiding undertreatment of chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs 16 (4): E133-41, 2012. [PUBMED Abstract]
6. Dranitsaris G, Bouganim N, Milano C, et al.: Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11 (1): 14-21, 2013. [PUBMED Abstract]
7. Kris MG, Urba SG, Schwartzberg LS: Clinical roundtable monograph. Treatment of chemotherapy-induced nausea and vomiting: a post-MASCC 2010 discussion. Clin Adv Hematol Oncol 9 (1): suppl 1-15, 2011. [PUBMED Abstract]
8. Phillips RS, Gopaul S, Gibson F, et al.: Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane Database Syst Rev (9): CD007786, 2010. [PUBMED Abstract]
9. Olver I, Clark-Snow RA, Ballatori E, et al.: Guidelines for the control of nausea and vomiting with chemotherapy of low or minimal emetic potential. Support Care Cancer 19 (Suppl 1): S33-6, 2011. [PUBMED Abstract]
10. Hesketh PJ, Kris MG, Basch E, et al.: Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 35 (28): 3240-3261, 2017. [PUBMED Abstract]
11. Geling O, Eichler HG: Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 23 (6): 1289-94, 2005. [PUBMED Abstract]
12. Fleishman SB, Mahajan D, Rosenwald V, et al.: Prevalence of Delayed Nausea and/or Vomiting in Patients Treated With Oxaliplatin-Based Regimens for Colorectal Cancer. J Oncol Pract 8 (3): 136-40, 2012. [PUBMED Abstract]

Prevention and Management of Acute or Delayed Nausea and Vomiting

In This Section

• Competitive Dopamine (D2) Antagonists
  • Phenothiazines
  • Butyrophenones
  • Substituted benzamides
• 5-HT3 Receptor Antagonists
  • Comparison of agents
  • Ondansetron
  • Granisetron
  • Dolasetron
  • Palonosetron
• NK-1 Receptor Antagonists (Substance P Antagonists)
  • Aprepitant/fosaprepitant
  • Netupitant
  • Rolapitant
• Corticosteroids
• Benzodiazepines
• Olanzapine
• Other Pharmacologic Agents
  • Cannabis
  • Ginger
• Multiday Chemotherapy
• High-Dose Chemotherapy with Stem Cell Transplantation
• Current Clinical Trials

Several organizations—including the American Society of Clinical Oncology, the National Comprehensive Cancer Network, and the Pediatric Oncology Group of Ontario—have published antiemetic guidelines for their members. It is not the policy of PDQ to endorse specific guidelines, but examples can be found in the literature.[1-4]

Antiemetic agents are the most common intervention in the management of treatment-related nausea and vomiting (N&V). 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.[5,6] Many antiemetics act by competitively blocking receptors for these substances, thereby inhibiting stimulation of peripheral nerves at the CTZ and possibly at the vomiting center.

Current guidelines [2,7] recommend that prechemotherapy management of chemotherapy-induced N&V (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-hydroxytryptamine-3 (5-HT3) receptor antagonist, neurokinin-1 (NK-1) receptor antagonist, and dexamethasone with or without olanzapine is recommended prechemotherapy. Aprepitant (if chosen as the NK-1 receptor antagonist prechemotherapy), olanzapine, and dexamethasone are recommended for the prevention of delayed emesis. Guidelines differ with respect to using a three- or four-drug regimen for prophylaxis for highly emetogenic chemotherapy. One guideline includes the option of omitting an NK-1 antagonist completely if dexamethasone, palonosetron, and olanzapine are used.[7]

For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT3 receptor antagonist and dexamethasone is used prechemotherapy. Patients receiving carboplatin (area under the curve [AUC] ≥4 mg/mL) may also receive an NK-1 receptor antagonist. Postchemotherapy, a 5-HT3 receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.

For regimens with low emetogenic potential, dexamethasone or a 5-HT3 receptor antagonist is recommended. For regimens with minimal emetogenic risk, no prophylaxis is recommended.[2,7]

Antiemetic guidelines [2,7] 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.[8]

Studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners.[8-10] One study suggested that patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea.[11] In addition, the current and new agents have been used as prophylaxis for acute and delayed CINV and have not been studied for use in established CINV. One study reported the effective use of intravenous (IV) palonosetron and dexamethasone for the prevention of CINV in patients receiving multiple-day chemotherapy.[12]

Pre- and postchemotherapy recommendations by emetogenic potential are summarized in Table 2.

Table 2. Antiemetic Recommendations by Emetic Risk Categoriesa,b

Emetic Risk Category	ASCO Guidelines	MASCC Guidelines	NCCN Guidelines
5-HT3 = 5-hydroxytryptamine-3; ASCO = American Society of Clinical Oncology; AUC = area under the curve; MASCC = Multinational Association of Supportive Care in Cancer; NCCN = National Comprehensive Cancer Network; NK-1 = neurokinin-1.
aAdapted from National Comprehensive Cancer Network,[7] Roila et al.,[13] and Hesketh et al.[2]
bOrder of listed antiemetics does not reflect preference.
High (>90%) risk	4-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, dexamethasone, and olanzapine recommended prechemotherapy	3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy	3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone prechemotherapy
			Note: Depending on NK-1 antagonist, dosing may be ≥1 day
	Olanzapine and dexamethasone to be continued on days 2–4		OR: Olanzapine (10 mg), palonosetron (0.25 mg), and dexamethasone (12 mg) prechemotherapy, followed by olanzapine (10 mg) daily on days 2–4
	For anthracycline and cyclophosphamide combinations only, olanzapine to be continued on days 2–4		OR: Four-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, dexamethasone, and olanzapine recommended prechemotherapy
	Note: Depending on NK-1 antagonist, dosing may be ≥1 day		Olanzapine and dexamethasone to be continued on days 2–4
			Note: Depending on NK-1 antagonist, dosing may be ≥1 day
Moderate (30%–90%) risk	Carboplatin AUC ≥4 mg/mL per min; 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy	For carboplatin-containing regimens, 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy	2-drug combination of 5-HT3 receptor antagonist and dexamethasone followed by dexamethasone (8 mg ) on days 2–3 OR: 5-HT3 receptor antagonist monotherapy on days 2–3
	For patients receiving chemotherapies of moderate emetic risk excluding carboplatin AUC ≥4 mg/mL per min, 2-drug combination of 5-HT3 receptor antagonist and dexamethasone recommended prechemotherapy	For patients receiving chemotherapies of moderate emetic risk excluding carboplatin, 2-drug combination of 5-HT3 receptor antagonist and dexamethasone recommended prechemotherapy	OR: Olanzapine (10 mg), palonosetron (0.25 mg), and dexamethasone (12 mg) prechemotherapy, followed by olanzapine (10 mg daily) on days 2–3
	For patients receiving cyclophosphamide, doxorubicin, oxaliplatin, and other moderate-emetic-risk antineoplastic agents known to cause delayed nausea, dexamethasone may be offered on days 2–3 for prevention of delayed emesis	For patients receiving cyclophosphamide, doxorubicin, or oxaliplatin, dexamethasone may be offered on days 2–3 for prevention of delayed emesis	OR: 3-drug combination of NK-1 antagonist, 5-HT3 receptor antagonist, and dexamethasone recommended prechemotherapy, followed by dexamethasone (8 mg ) on days 2–3
			Note: depending on NK-1 antagonist, dosing may be ≥1 day
Low (10%–30%) risk	Single dose of 5-HT3 receptor antagonist or dexamethasone (8 mg) recommended	Single dose of 5-HT3 receptor antagonist or dexamethasone or dopamine antagonist recommended	Single dose of 5-HT3 receptor antagonist or dexamethasone (8 mg) or metoclopramide (10–20 mg) or prochlorperazine (10 mg) recommended
Minimal (<10%) risk	No antiemetic administered routinely pre- or postchemotherapy	No routine prophylaxis recommended	No routine prophylaxis recommended

Most drugs with proven antiemetic activity can be categorized into one of the following groups:

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

Although all routes of administration are listed for each drug in Table 3, the intramuscular (IM) route is used only when no other access is available. IM 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 one or two doses of a drug are to be given.

Table 3. Prevention of Acute or Delayed CINV

ENLARGE

Drug Category	Medication	Dose	Available Route	Comment(s)	Reference(s)
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; CINV = chemotherapy-induced nausea and vomiting; EPS = extrapyramidal symptoms; IM = intramuscular; IV = intravenous; NK-1 = neurokinin-1; PO = oral; PR = rectal; qd = every day; SL = sublingual; SQ = subcutaneous.
aDolasetron may be difficult to obtain from the manufacturer.
Dopamine antagonists: phenothiazines	Chlorpromazine	10–25 mg PO q4–6h	PO, IM	Prolongs QT interval	[14,15][Level of evidence: II]
		25–50 mg IM q3–4h
	Prochlorperazine	25 mg PR q12h	PO, IM, IV, PR	Less sedation, but increased risk of EPS	[14]
		5–10 mg PO/IM/IV q6–8h
	Promethazine	12.5–25 mg q4–6h	PO, IM, IV, PR	Vesicant	[14][Level of evidence: IV]
				Weak antiemetic
Dopamine antagonists: butyrophenones	Haloperidol	1–4 mg q6h	PO, IV, IM	Used for treatment	[16][Level of evidence: III]
				Rarely used for prophylaxis
				Prolongs QT interval
	Droperidol	0.625–2.5 mg/dose	IV	Prolongs QT interval	[14,16][Level of evidence: III]
				Used primarily for treatment
Dopamine antagonists: substituted benzamides	Metoclopramide	Prevention of CINV: 1–2 mg/kg IV x1 dose prechemotherapy; then x2 doses q2h; then x3 doses q3h	PO, IM, IV	EPS associated with higher doses; patients <30 y	[14]
				Pretreat with diphenhydramine to prevent EPS
		Treatment of CINV: 10–40 mg PO q4–6h; up to 0.5 mg/kg PO q6h		Enhances gastric emptying
	Trimethobenzamide	300 mg PO q6–8h	PO, IM	Unavailable in United States	[14,17][Level of evidence: II]
		200 mg IM q6–8h
Serotonin (5-HT3) receptor antagonists	Dolasetrona	100 mg within 1 h prechemotherapy	PO	IV form withdrawn from market due to QTc prolongation	[14]
	Granisetron	1–2 mg PO or 10 µg/kg up to 1 mg IV within 1 h of chemotherapy	IV, PO, topical, SQ	Transdermal patch applied 24 h prechemotherapy; may be left in place ≤1 wk	[14]
		3.1 mg/24 h transdermally
		10 mg SQ ≥30 min prechemotherapy		SQ extended release should not be given more than once q7d
	Ondansetron	0.15 mg/kg IV 30 min prechemotherapy; then may be repeated 4 and 8 h later; maximum: 16 mg/24 h	PO, IV	Doses >16 mg not recommended due to QTc prolongation	[14,16][Level of evidence: I]
		24 mg PO 30 min before highly emetogenic single-day chemotherapy
		8 mg PO 30 min before moderate-emetogenic-risk chemotherapy, followed in 8 h by 8 mg then 8 mg PO q12h for 1–2 d		Post-approval studies show 8 mg IV equivalent to larger doses
	Palonosetron	0.25 mg IV or 0.5 mg PO 30 min prechemotherapy day 1	IV, PO		[14]
Substance P antagonists (NK-1 receptor antagonists)	Aprepitant	125 mg prechemotherapy day 1, then 80 mg daily x2 d	PO	CYP3A4 enzyme inhibitor	[14]
				CYP2C9 enzyme inducer
	Aprepitant, emulsion	130 mg prechemotherapy day 1	IV	Dose equivalent to fosaprepitant 150 mg	[14]
				CYP3A4 enzyme inhibitor
				CYP2C9 enzyme inducer
	Fosaprepitant	150 mg prechemotherapy day 1	IV	CYP3A4 enzyme inhibitor	[14]
				CYP2C9 enzyme inducer
	Netupitant (combined with palonosetron)	Netupitant 300 mg/palonosetron 0.5 mg prechemotherapy day 1	PO/IV	CYP3A4 enzyme inhibitor	[14]
	Rolapitant	180 mg prechemotherapy day 1	PO/IV	Anaphylactic reactions have occurred with IV infusion	[14]
				Doses must be separated by ≥14 d
				CYP2D6 enzyme inhibitor
Corticosteroids	Dexamethasone	12–20 mg before high-emetic-risk chemotherapy, followed by 8 mg 1–2 times/d for 3 d	PO, IV	Combined with a 5-HT3 receptor antagonist	[14]
		8 mg before moderate-emetic-risk chemotherapy, followed by 8 mg/d for 2 d		When given with aprepitant, fosaprepitant, or netupitant, 12 mg = 20 mg on day 1, and 8 mg is equivalent on subsequent days due to drug interaction
	Methylprednisolone	0.5–1 mg/kg 30 min pre- and 4 and 8 h postchemotherapy	PO, IV	Maximum 4 mg/kg/d; may also be given as single dose prechemotherapy	[16][Level of evidence: III]
Benzodiazepines	Alprazolam	0.25–1 mg q6–8h	PO	Shortest half-life in drug class	[14,18][Level of evidence: I]
	Lorazepam	0.5–2 mg q6h	PO, SL, IM, IV	Most-commonly used in drug class	[14]
Atypical antipsychotics	Olanzapine	Prevention of acute and delayed CINV in combination with 5-HT3 antagonist, dexamethasone, and NK-1 antagonist: 10 mg PO qd days 1–4	PO	Consider giving at bedtime due to sedation	[19][Level of evidence: I]
		Treatment of breakthrough CINV: 10 mg PO daily x3 d			[20][Level of evidence: I]
Other pharmacologic agents	Dronabinol	5 mg/m2 PO 1–3 h prechemotherapy, followed every 2–4 h by same dose, up to 4–6 doses/d	PO		[14]
		Dose may be increased in increments of 2.5 mg/m2, up to maximum 15 mg/m2
	Nabilone	1–2 mg bid, maximum 6 mg/d in 3 doses	PO	May be continued up to 48 h postchemotherapy	[14]
	Cannabis	No current data on dosing	Inhaled, PO	Currently, not enough data to recommend Cannabis products for prevention/treatment of CINV	[21][Level of evidence: IV]
	Ginger	0.5–2 g/d prechemotherapy	PO	Current literature demonstrates conflicting efficacy results	[22,23][Level of evidence: II]

Competitive Dopamine (D2) Antagonists

Phenothiazines

Phenothiazines act on dopaminergic receptors at the CTZ, possibly at other central nervous system (CNS) centers, and peripherally.

In selecting phenothiazines, the primary consideration is assessing differences in adverse effect profiles, which correlate with the structural classes of the drugs. Generally, aliphatic phenothiazines (e.g., chlorpromazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine) are associated with less sedation but higher incidence of extrapyramidal symptoms (EPS) (acute dystonias, akathisia, neuroleptic malignant syndrome [uncommon], and, rarely, akinesias and dyskinesias). Marked hypotension may also result if IV doses are administered rapidly at high doses. The concomitant use of H1 blockers, such as diphenhydramine, can often decrease the risk and severity of EPS. Phenothiazines may be of particular value in treating patients who experience delayed N&V with cisplatin regimens.[24-28][Level of evidence: I] Given their anticholinergic properties, phenothiazines are listed among the American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.[29]

Butyrophenones

Droperidol and haloperidol represent butyrophenones, 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 some antiemetic activity. Droperidol is typically administered from 1 mg to 2.5 mg IM or IV every 2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[30,31] Haloperidol is typically administered from 1 mg to 4 mg IM, IV, or orally, every 2 to 6 hours.[32] Results of a small, uncontrolled, open-label study showed some efficacy for haloperidol in palliative care patients.[33] Both agents may produce EPS, akathisia, hypotension, and sedation.

Substituted benzamides

Metoclopramide is a substituted benzamide, which, before serotonin (5-HT3) receptor antagonists were introduced, was considered the most effective antiemetic agent against highly emetogenic chemotherapy. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given IV at high doses, 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. 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 that of multiple intermittent dosing schedules.[34-36]

Metoclopramide is associated with akathisia and dystonic EPS; akathisia is seen more frequently in patients older than 30 years, and dystonic EPS are seen more commonly in patients younger than 30 years. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize EPS.[37] While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia is best treated by lowering the metoclopramide dose, changing to a different agent, or adding a benzodiazepine.

Trimethobenzamide is believed to act centrally on the CTZ by blocking emetic impulses. It has been studied in a limited number of oncology patients experiencing nausea from various chemotherapy regimens. Compared with placebo, trimethobenzamide 200 mg IM every 6 hours for 2 days significantly reduced episodes of N&V.[17]

5-HT3 Receptor Antagonists

Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron, and palonosetron—are available in the United States. Agents in this class are thought to prevent N&V 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.[38-40] The 5-HT3 receptor antagonists may also block serotonin stimulation at the CTZ and other CNS structures. Major side effects of this class of medications include mild headache and constipation. Multiple studies have shown that the 5-HT3 receptor antagonists are most effective when given in conjunction with steroids.

Comparison of agents

Studies suggest that there are no major differences in efficacy or toxicity of the three first-generation 5-HT3 receptor antagonists (dolasetron, granisetron, and ondansetron) in the treatment of acute CINV. These three agents are equivalent in efficacy and toxicity when used in appropriate doses.[41,42]; [43][Level of evidence: I] 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 on days 2 to 5 postchemotherapy (delayed phase).

Palonosetron, the second-generation 5-HT3 receptor antagonist, has been approved for the control of acute emesis with highly and moderately emetogenic chemotherapy and approved for delayed emesis in patients receiving moderately emetogenic chemotherapy.[44]; [45][Level of evidence: I]

Despite the use of both first-generation and second-generation 5-HT3 receptor antagonists, the control of acute CINV, and especially delayed N&V, is suboptimal, and there is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.[8,46-48]

Ondansetron

Several studies have demonstrated that ondansetron produces an antiemetic response that is equal or superior to that of high doses of metoclopramide, but ondansetron has an improved toxicity profile, compared with that of dopaminergic antagonist agents.[49-52][Level of evidence: I]; [53,54] A randomized trial of ondansetron, 8 mg and 32 mg, given prophylactically to patients receiving cisplatin found no difference between the doses.[55] A single-center retrospective chart review has reported ondansetron-loading doses of 16 mg/m2 IV (maximum, 24 mg) to be safe in infants, children, and adolescents.[56] However, data reported to the U.S. Food and Drug Administration (FDA) raise concerns about QT prolongation and potentially fatal arrhythmias with a single 32-mg IV dose. Current drug labeling calls for a maximum single 16-mg IV dose.[57]

Currently, the oral and injectable ondansetron formulations are approved for use without dosage modification in patients older than 4 years, including elderly patients 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. Ondansetron clearance is diminished in patients with severe hepatic insufficiency; therefore, such patients receive a single injectable or oral dose no higher than 8 mg. There is currently no information 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/h for 24 h) or oral administration have also been evaluated.[58]

The major adverse effects of ondansetron include the following:[59]

• Headache (which can be treated with mild analgesics).
• Constipation.
• Fatigue.
• Dry mouth.
• Transient asymptomatic elevations in liver function tests (alanine and aspartate transaminases), which may be related to concurrent cisplatin administration.

Ondansetron has been etiologically implicated in a few case studies involving thrombocytopenia, renal insufficiency, and thrombotic events.[60] Rare electrocardiogram changes in the form of QTc prolongation may occur. In addition, a few case reports have implicated ondansetron in causing EPS. However, it is not clear in some cases whether the events described were in fact EPS; in other reports, the evidence is confounded by concurrent use of other agents that are known to produce EPS. 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 N&V.[61] Randomized, double-blind, placebo-controlled trials support the addition of aprepitant, an NK-1 receptor antagonist, for additional mitigation of N&V.[62,63][Level of evidence: I]

Granisetron

Granisetron has demonstrated efficacy in preventing and controlling N&V at a broad range of doses. In the United States, granisetron injection, extended-release injection, transdermal patch, 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 is equally efficacious and equally safe.[61-64][Level of evidence: I]

The subcutaneous extended-release formulation of granisetron was compared with palonosetron in the prevention of CINV for patients receiving moderately or highly emetogenic chemotherapy in a randomized, double-blind noninferiority phase III trial.[65] Patients were randomly assigned to receive IV palonosetron, 0.25 mg; or subcutaneous granisetron, 5 mg or 10 mg. Patients who received palonosetron in cycle 1 were then randomly assigned to receive granisetron in cycles 2 through 4. Both subcutaneous doses of granisetron were noninferior to palonosetron in cycle 1 of moderately emetogenic chemotherapy (74.8% and 76.9% for granisetron 5 mg and 10 mg, respectively, vs. 75.0% for palonosetron) and highly emetogenic chemotherapy (77.7% and 81.3% for granisetron 5 mg and 10 mg, respectively, vs. 80.7% for palonosetron). Superiority of subcutaneous granisetron versus palonosetron in the prevention of delayed CINV after highly emetogenic chemotherapy was not established.

Currently, granisetron is approved for use without dosage modification in patients older than 2 years, including elderly patients and patients with hepatic and renal insufficiency.

Dolasetron

Oral formulations of dolasetron are indicated for the prevention of N&V associated with moderately emetogenic cancer chemotherapy, including initial and repeat courses; however, the drug may be difficult to obtain from the manufacturer. Oral dolasetron may be dosed as 100 mg within 1 hour before chemotherapy. Dolasetron was given IV or orally at 1.8 mg/kg as a single dose approximately 30 minutes before chemotherapy; however, injection formulations are no longer approved for CINV because of the risk of QTc interval prolongation.[66]

The effectiveness of oral dolasetron in the prevention of CINV has been proven in a large randomized, double-blind, comparative trial of 399 patients.[67][Level of evidence: I] Oral dolasetron was administered in the range of 25 to 200 mg 1 hour before chemotherapy. The other study arm consisted of oral ondansetron (8 mg) administered 1.5 hours before chemotherapy and every 8 hours after chemotherapy for a total of three doses. Rates of complete response (CR), defined as no emetic episodes and no use of escape antiemetic medications, improved with increasing doses of dolasetron. Both dolasetron 200 mg and ondansetron had significantly higher CR rates than did dolasetron 25 or 50 mg.

Palonosetron

Palonosetron is a 5-HT3 receptor antagonist (second generation) that has antiemetic activity at both central and GI sites. Palonosetron is FDA approved for the prevention of acute N&V associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy and for the prevention of delayed N&V associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Compared with the older 5-HT3 receptor antagonists, palonosetron 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.[68][Level of evidence: I] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[69-73]

In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and delayed periods for patients who received 0.25 mg of palonosetron alone, compared with either ondansetron or dolasetron alone.[44]; [45][Level of evidence: I] 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,[74][Level of evidence: I] 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 CINV 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 [75] reported that the CR rates for both acute and delayed CINV were maintained with single IV doses of palonosetron without concomitant corticosteroids.

NK-1 Receptor Antagonists (Substance P Antagonists)

Substance P, found in the vagal afferent neurons in the nucleus tractus solitarius, the abdominal vagus, and the area postrema, induces vomiting. NK-1 receptor antagonists, including aprepitant, fosaprepitant, netupitant, and rolapitant block substance P from binding the NK-1 receptor. In combination with a 5-HT3 receptor antagonist and a corticosteroid, NK-1 receptor antagonists are indicated for the prevention of acute and delayed N&V associated with initial and repeat courses of high and moderately emetogenic chemotherapy. There have been no randomized trials comparing the individual NK-1 receptor antagonists. All are considered effective at their FDA-approved doses.

Aprepitant/fosaprepitant

Clinical trials [76-79] demonstrated that the addition of aprepitant to a 5-HT3 receptor antagonist plus dexamethasone before cisplatin chemotherapy improved the control of acute emesis, compared with a 5-HT3 receptor antagonist plus dexamethasone; this regimen also improved the control of delayed emesis, compared with placebo. In two randomized, double-blind, parallel, controlled studies, patients received cisplatin (≥70 mg/m2) and were randomly assigned to receive either standard therapy with ondansetron and dexamethasone prechemotherapy and dexamethasone on days 2 to 4 postchemotherapy; or standard therapy plus aprepitant prechemotherapy on days 2 and 3.[80,81][Level of evidence: I] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute and the delayed periods. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[82][Level of evidence: I] Finally, aprepitant has been shown to be efficacious in preventing N&V in breast cancer patients receiving highly emetogenic chemotherapy with cyclophosphamide and doxorubicin.[83]

The benefit of aprepitant has been demonstrated outside of highly emetogenic chemotherapy. The addition of aprepitant to ondansetron and dexamethasone before moderately emetogenic chemotherapy versus ondansetron and dexamethasone alone resulted in improved CINV outcomes.[84-86] An alternative dosing strategy was evaluated in a randomized, double-blind, placebo-controlled, phase III cross-over study in patients receiving 5-day cisplatin combination chemotherapy for germ cell tumors.[87] In addition to standard antiemetic therapy, patients received aprepitant 125 mg on day 3 followed by aprepitant 80 mg on days 4 through 7. There was a significant improvement in CINV CR with the three-drug regimen.

Fosaprepitant dimeglumine, a water-soluble, phosphorylated analog of aprepitant, is rapidly converted to aprepitant after IV administration.[88] Fosaprepitant is approved as a single dose of 150 mg before chemotherapy on day 1, as an alternative to the 3-day oral aprepitant regimen. As demonstrated in a randomized, double-blind study of patients receiving cisplatin chemotherapy, single-dose IV fosaprepitant (150 mg) given with ondansetron and dexamethasone was noninferior to the standard 3-day dosing of oral aprepitant in preventing CINV.[88] Fosaprepitant is formulated with polysorbate 80, a solubilizing agent, which can cause rare but serious hypersensitivity reactions.[89,90] Aprepitant is also available as a parenteral emulsion form, which has a reduced risk of thrombophlebitis and hypersensitivity reactions.[91]

Netupitant

Netupitant is a competitive antagonist to the NK-1 receptor that is marketed as an oral or IV fixed-combination product containing 300 mg of netupitant and 0.5 mg of palonosetron (NEPA). It is given with dexamethasone before chemotherapy for the prevention of both acute and delayed CINV. This drug combination has been used successfully for prevention of CINV in a single cycle of both highly and moderately emetogenic chemotherapy regimens.[92,93] The antiemetic benefit of NEPA was demonstrated throughout multiple cycles of chemotherapy in a randomized, double-blind, controlled trial.[94][Level of evidence: I] Patients starting combination anthracycline/cyclophosphamide regimens were randomly assigned to receive oral fixed-dose NEPA with 12 mg of dexamethasone or 0.5 mg of oral palonosetron with 20 mg of dexamethasone. The percentage of patients with a CR (defined as no emesis, no rescue medication) was significantly greater for NEPA than for oral palonosetron for cycles 1 to 4. The most common treatment-related side effects were headache and constipation, which were similar between the two arms. Similarly, NEPA has been compared with granisetron and aprepitant in patients receiving highly emetogenic chemotherapy. In a phase III, randomized, double-blind study, a single dose of NEPA was shown to be noninferior to a 3-day regimen of granisetron and aprepitant. Additionally, significantly more patients did not need rescue medications when they received NEPA (96.6%) compared with those who received granisetron plus aprepitant (93.5%). Toxicities were similar between treatment arms.[95][Level of evidence: I]

Rolapitant

Rolapitant is an oral competitive NK-1 receptor inhibitor. It is approved for the prevention of delayed N&V associated with highly and moderately emetogenic chemotherapy. In addition to granisetron and dexamethasone, rolapitant significantly increases CINV CR (no emesis, no rescue) versus standard therapy plus placebo for patients receiving both highly and moderately emetogenic chemotherapy. Unlike other drugs in its class, rolapitant has no effect on cytochrome P450 3A4 enzymes; therefore, no dose adjustment for dexamethasone is required.[96-98] The IV formulation has been associated with hypersensitivity reactions, including anaphylaxis, which have limited its use.[99]

Corticosteroids

Steroids are commonly used in combination with other antiemetics. 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 N&V and may improve patients’ mood, thus producing a subjective sense of well-being or euphoria (although they also can cause depression and anxiety). Steroids are sometimes used as single agents against mildly emetogenic chemotherapy but are more often used in antiemetic drug combinations.[100,101][Level of evidence: I][102]

Steroids are given orally or intravenously before chemotherapy and may be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice for N&V in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally or intravenously in the dose range of 8 mg to 40 mg (pediatric dose, 0.25–0.5 mg/kg).[103,104] Methylprednisolone is also administered orally or IV at doses and schedules that vary from 40 mg to 500 mg every 6 to 12 hours for up to 20 doses.[101,105]

Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:[106-108]

• 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.
• 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 (e.g., overall survival or efficacy of chemotherapy).[109] As previously shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT3–blocking agents.[106,110] If administered intravenously, dexamethasone may be given over 10 to 15 minutes because rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perineal and/or rectal pain.[111-114]

Benzodiazepines

Benzodiazepines such as lorazepam and alprazolam have become recognized as valuable adjuncts in the prevention and treatment of anxiety and the symptoms of anticipatory N&V associated with chemotherapy, especially with the highly emetogenic regimens given to children.[106-108] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents; therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents.[115] Benzodiazepines presumably act on higher CNS structures, the brainstem, and spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic effects. In addition, benzodiazepines markedly decrease the severity of EPS, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.

The adverse effects of lorazepam include sedation, perceptual and vision disturbances, anterograde amnesia, confusion, ataxia, and depressed mental acuity.[116];[117][Level of evidence: I][118,119] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.[18]

Olanzapine

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-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at alpha-1 adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H1 receptors.[120] Common side effects include the following:[121,122]

• Sedation.
• Dry mouth.
• Increased appetite.
• Weight gain.
• Postural hypotension.
• Dizziness.

Olanzapine’s activity at multiple receptors, particularly at the D2 and 5-HT3 receptors that appear to be involved in N&V, suggests that it may have significant antiemetic properties.[123][Level of evidence: II] Subsequent studies have shown the effectiveness of olanzapine as a CINV antiemetic.[124,125][Level of evidence: II] A large study [126][Level of evidence: I] demonstrated that in patients receiving either highly emetogenic chemotherapy or moderately emetogenic chemotherapy, the addition of olanzapine to azasetron and dexamethasone improved the CR of delayed CINV.

A randomized, double-blind, phase III trial evaluated olanzapine versus placebo in addition to standard antiemetics for the prevention of CINV associated with highly emetogenic chemotherapy.[19][Level of evidence: I] Chemotherapy-naïve patients receiving either cisplatin at least 70 mg/m2 of body surface area (BSA) with or without additional agents, or doxorubicin 60 mg/m2 of BSA with cyclophosphamide 600 mg/m2 of BSA, were randomly assigned to receive olanzapine 10 mg orally on days 1 through 4 or matching placebo with guideline-directed antiemetics. The antiemetic regimen included an NK-1 antagonist (fosaprepitant or aprepitant), 5-HT3 antagonist (palonosetron, granisetron, or ondansetron), and dexamethasone 12 mg on day 1 followed by 8 mg orally daily on days 2 through 4. Patients were stratified by sex, chemotherapy regimen, and the specific 5-HT3 antagonist chosen. The primary endpoint, no nausea, was defined as a score of 0 on the visual analog scale of 0 to 10 and assessed at three time points postchemotherapy: early, 0 to 24 hours; later, 25 to 120 hours; and overall, 0 to 120 hours.

The percentage of patients experiencing no nausea was significantly higher in the olanzapine group than in the placebo group at the early (74% vs. 45%; P = .002), later (42% vs. 25%; P = .002), and overall time points (37% vs. 22%; P = .002). CR (no emesis, no rescue) rate and freedom from clinically significant nausea (a score lower than 3 on the visual analog scale of 0–10) were also significantly improved with the addition of olanzapine at all time points. Patients receiving olanzapine reported increased sedation from baseline on day 2, which resolved on days 3 through 5. On the basis of these data and additional clinical trials, olanzapine appears to be safe and effective in controlling acute and delayed CINV in patients receiving highly emetogenic and moderately emetogenic chemotherapy.[127,128]

Other Pharmacologic Agents

Cannabis

The plant Cannabis contains more than 60 different types of cannabinoids, or components that have physiologic activity. The most popular, and perhaps the most psychoactive, is delta-9-tetrahydrocannabinol (delta-9-THC).[129] There are two FDA-approved Cannabis products for CINV:

• Dronabinol (a synthetic delta-9-THC), as prophylaxis for CINV, 5 mg/m2 orally 1 to 3 hours before chemotherapy and every 2 to 4 hours after chemotherapy, for a total of no more than 6 doses per day.
• Nabilone, for CINV that has failed to respond to other antiemetics, 1 to 2 mg orally twice a day.

With respect to CINV, Cannabis products probably target cannabinoid-1 (CB-1) and CB-2 receptors, which are in the CNS.[130]

Much of the research on agents in this class was conducted in the late 1970s and 1980s and compared nabilone, dronabinol, or levonantradol to older antiemetic agents that targeted the dopamine receptor, such as prochlorperazine (Compazine) and metoclopramide (Reglan).[131-135] This group of studies demonstrated that cannabinoids were as effective for moderately emetogenic chemotherapy as dopaminergic antiemetics or were more effective than placebo.[129] Side effects included euphoria, dizziness, dysphoria, hallucinations, and hypotension.[129] Despite earlier reports of efficacy, in at least one study, patients did not significantly prefer nabilone because of the side effects.[131]

Since the 1990s, research in N&V has elucidated newer and more physiologic targets, namely 5-HT3 and NK-1 receptors. Subsequently, 5-HT3 and NK-1 receptor antagonists have become standard prophylactic therapy for CINV. Studies investigating the role of Cannabis extract and cannabinoids with these newer agents are few; therefore, limited conclusions can be drawn. In published trials, however, Cannabis extract and cannabinoids have not demonstrated more efficacy than 5-HT3 receptor antagonists, and synergistic or additive effects have not been fully investigated.[136,137]

In summary, the place of Cannabis and cannabinoids in today’s arsenal of antiemetics for the prevention and treatment of CINV is not known. Discussions with patients about its use may include responses to available agents, known side effects of Cannabis, and an assessment of the risks versus benefits of this therapy.[138]

Refer to the PDQ summary on Cannabis and Cannabinoids for more information.

Ginger

There are conflicting data on the efficacy of ginger for prophylaxis of CINV. A phase III, randomized, dose-finding trial of 576 patients with cancer evaluated 0.5 g, 1 g, and 1.5 g of ginger versus placebo in twice-a-day dosing for the prevention of acute nausea (defined as day 1 postchemotherapy) in patients experiencing some level of nausea (as measured on an 11-point scale) caused by their current chemotherapy regimen, despite standard prophylaxis with a 5-HT3 receptor antagonist. Patients began taking ginger or placebo capsules 3 days before each chemotherapy treatment and continued them for 6 days. For average nausea, 0.5 g of ginger was significantly better than placebo; both 0.5 g and 1 g were significantly better than placebo for “worst nausea.” Effects for delayed N&V were not significant. This trial did not control for emetogenicity of the chemotherapy regimens. Adverse events were infrequent and were not severe.[22] Conversely, data on ginger used to prevent N&V have not been as promising. A randomized, double-blind, placebo-controlled study evaluated the use of ginger 160 mg per day in patients receiving high-dose cisplatin (>50 mg/m2). Patients (N = 251) were assigned to receive either ginger or placebo. The incidence of delayed nausea, intercycle nausea, and anticipatory nausea did not differ between the two treatment arms.[139]

Multiday Chemotherapy

Regimens that include chemotherapy doses on multiple sequential days (multiday chemotherapy) present a unique challenge to preventing CINV because after the first dose of chemotherapy, nausea may be both acute and delayed. Although there is no standard antiemetic regimen for multiday chemotherapy, a corticosteroid and a 5-HT3 antagonist should be given with each day of highly and moderately emetogenic chemotherapy.[7,140] Evidence demonstrates benefit for the addition of an NK-1 antagonist to highly and moderately emetogenic multiday chemotherapy.[2,7,13,140] The choice of antiemetic drugs and their schedule should be matched to the emetogenicity of the individual chemotherapy agents and their sequence. In addition, the length of delayed nausea varies and will depend on the emetogenicity of the last day’s chemotherapy.

Dexamethasone is scheduled on each day of a multiday chemotherapy regimen, and for 2 to 3 days after if there is risk of delayed nausea. Additional dexamethasone is not necessary if the chemotherapy regimen contains a corticosteroid. It is not known whether dexamethasone 20 mg given each day of a 5-day cisplatin regimen provides additional antiemetic benefit, and it may add toxicity.[13,141] Therefore, an alternative dexamethasone schedule (20 mg on days 1 and 2 followed by 8 mg twice daily on days 6 and 7, and 4 mg twice daily on day 8), based on the timing of CINV and to reduce the total steroid dose, has been studied in patients receiving 5-day cisplatin regimens.[12,13]

Standard antiemetic prophylaxis includes a 5-HT3 antagonist given before the first chemotherapy dose each day of a multiday chemotherapy regimen.[2,7,13,140] No 5-HT3 antagonist is favored over other agents in the class for multiday chemotherapy. Palonosetron is a 5-HT3 antagonist with a longer half-life and higher receptor-binding affinity than other members in its class, allowing it to be given less frequently.[72] A prospective, uncontrolled trial demonstrated that palonosetron, as a single IV dose with dexamethasone 20 mg before two 3-day chemotherapy regimens, resulted in an 80% CR (no vomiting, no rescue).[142] Palonosetron was also studied with dexamethasone as prophylaxis for a 5-day cisplatin-based regimen for germ cell tumors.[12] When palonosetron plus dexamethasone was given on days 1, 3, and 5, 51% of patients experienced no emesis on days 1 to 5, and 83% experienced no emesis on days 6 to 9. Alternative methods of 5-HT3 antagonist delivery have been studied.

Granisetron as a 7-day continuous transdermal patch was compared to daily oral granisetron in patients receiving multiday chemotherapy in a double-blind, phase III, noninferiority study.[64] The patch demonstrated complete control in 60% of patients, while the oral formulation did so in 65% of patients, achieving noninferiority.

The NK-1 antagonist aprepitant and its IV formulation, fosaprepitant, have been studied with multiday chemotherapy in dosing schedules that differ from their FDA-approved schedules. A nonrandomized trial evaluated the use of aprepitant, granisetron, and dexamethasone for CINV prophylaxis with 3- and 5-day highly and moderately emetogenic chemotherapy.[143] Aprepitant was given at 125 mg orally before the first dose of chemotherapy, then 80 mg orally on each day of chemotherapy and for 2 following days (total, 5–7 days). CR was seen in 57.9% and 72.5% of patients receiving highly and moderately emetogenic chemotherapy, respectively. Similarly promising results were found in a subsequent single-arm trial looking at a 7-day oral aprepitant regimen with dexamethasone and a 5-HT3 antagonist for 5-day cisplatin-based chemotherapy.[144]

A randomized, double-blind, placebo-controlled crossover trial of aprepitant, a 5-HT3 antagonist, and dexamethasone was conducted in patients receiving 5-day cisplatin-based chemotherapy for germ cell tumors.[87] Oral aprepitant 125 mg was given on day 3, followed by oral aprepitant 80 mg daily on days 4 to 7. More patients achieved CR with aprepitant than with placebo, 42% versus 13% (P < .001). IV fosaprepitant 150 mg given on days 3 and 5 was studied in a small phase II trial evaluating its use with a 5-HT3 antagonist and dexamethasone in 5-day cisplatin-based chemotherapy.[145] Preliminary results showed a CR rate of 28.1%, lower than results of the oral aprepitant trial conducted by the same institution.

High-Dose Chemotherapy with Stem Cell Transplantation

Prevention of emesis during high doses of chemotherapy with or without total-body irradiation continues to be a challenging area of patient care.[146] Current guidelines address primarily single-day therapies; in addition, while emesis prevention for the multiple days of chemotherapy or radiation therapy used in this setting is based on single-day experiences, additional research is needed to improve symptom control for these patients.[146] This has led to the addition of NK-1 antagonists to the daily dosing of a serotonin antagonist plus dexamethasone.[146-148] Additional evidence is needed to determine optimal combinations as CR rates range as low as 30%.[148] Also, experience has primarily been with aprepitant; the newer NK-1 antagonists may offer additional benefit.

Overall, these antiemetic combinations are well tolerated, with most side effects involving the dexamethasone component; in addition, while drug interactions were originally a concern, they do not appear to be clinically significant.[149] Also, emesis is controlled to a much greater extent than is nausea, which continues to be challenging for many patients.[146,150] Finally, a randomized phase III trial studied the use of aprepitant, granisetron, and dexamethasone for the prevention of CINV in multiple myeloma patients receiving high-dose melphalan with autologous stem cell transplantation. A statistically positive benefit, without an increase in side effects, was seen in patients who received the three-drug regimen.[147]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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108. Hockenberry-Eaton M, Benner A: Patterns of nausea and vomiting in children: nursing assessment and intervention. Oncol Nurs Forum 17 (4): 575-84, 1990 Jul-Aug. [PUBMED Abstract]
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Nonpharmacologic Management of Nausea and Vomiting

Nonpharmacologic strategies are also used to manage nausea and vomiting (N&V). These include the following:

• Dietary alterations. (Refer to the Behavioral strategies for symptom management section in the Nutrition Therapy section of the PDQ summary on Nutrition in Cancer Care for more information.)
• Hypnosis.
• Acupuncture. (Refer to the PDQ summary on Acupuncture for more information.)
• Acupressure.
• Relaxation techniques.
• Behavioral therapy.
• Guided imagery.

Guided imagery, hypnosis, and systematic desensitization as means to progressive muscle relaxation have been the most frequently studied treatments for anticipatory N&V (ANV) and are the recommended treatments for this classically conditioned response. (Refer to the Treatment of ANV section of this summary for more information.)