Treatment-Related Nausea and Vomiting (PDQ®): Supportive care - Health Professional Information [NCI]

Skip to the navigation

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

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.
  2. Navari RM: Antiemetic control: toward a new standard of care for emetogenic chemotherapy. Expert Opin Pharmacother 10 (4): 629-44, 2009.
  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.
  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.

General Risk Factors and Etiologies

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.[1,2,3]

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 motion 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:[7,8,9]

  • 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]
Table 1. National Cancer Institute's Common Terminology Criteria for Adverse Events: N&Va
Adverse Event Grade Description
N&V = nausea and vomiting (emesis); TPN = total parenteral nutrition.
a Adapted from National Cancer Institute.[12]
b Definition: A disorder characterized by a queasy sensation and/or the urge to vomit.
c Definition: 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 1–2 episodes (separated by 5 min) in 24 h
2 3–5 episodes (separated by 5 min) in 24 h
3 ≥6 episodes (separated by 5 min) in 24 h; 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.
  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.
  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.
  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.
  5. Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: a review. Ann Oncol 2 (2): 107-14, 1991.
  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.
  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.
  8. Hesketh PJ: Chemotherapy-induced nausea and vomiting. N Engl J Med 358 (23): 2482-94, 2008.
  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.
  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.
  12. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Bethesda, Md: U.S. Department of Health and Human Services, National Institutes of Health, 2010. Available online. Last accessed January 12, 2017.

Anticipatory Nausea and Vomiting (ANV)

Prevalence

The prevalence of 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 (5-hydroxytryptamine-3 or 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.
  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.
  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.
  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.
  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.
  6. Reesal RT, Bajramovic H, Mai F: Anticipatory nausea and vomiting: a form of chemotherapy phobia? Can J Psychiatry 35 (1): 80-2, 1990.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  17. Tomoyasu N, Bovbjerg DH, Jacobsen PB: Conditioned reactions to cancer chemotherapy: percent reinforcement predicts anticipatory nausea. Physiol Behav 59 (2): 273-6, 1996.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

Acute or Delayed Chemotherapy-Induced Nausea and Vomiting (N&V) Etiology

Acute N&V

The incidence of acute N&V with moderate- or high-risk chemotherapy ranges from 30% to 90%.[1,2,3] 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.[5,6,7,8,9]

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 pregnancy-induced N&V.
  • Dehydration.
  • Malnutrition.
  • Recent surgery.
  • Radiation therapy.

The American Society of Clinical Oncology has developed a rating system for 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:
    • 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.
    • Daunorubicin.
    • Doxorubicin.
    • Epirubicin.
    • Idarubicin.
    • Ifosfamide
    • Irinotecan.
    • Oxaliplatin.
  • Low risk: Emesis that has been documented to occur in 10% to 30% of patients:
    • Bortezomib.
    • Cabazitaxel.
    • Cytarabine (<1,000 mg/m2).
    • Docetaxel.
    • Doxorubicin HCl liposome injection.
    • Etoposide.
    • Fluorouracil.
    • Gemcitabine.
    • Ixabepilone.
    • Methotrexate.
    • Mitomycin.
    • Mitoxantrone.
    • Paclitaxel.
    • Panitumumab.
    • Pemetrexed.
    • Temsirolimus.
    • Topotecan.
    • Trastuzumab.
  • Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:
    • Bevacizumab.
    • Bleomycin.
    • Busulfan.
    • Cetuximab.
    • Cladribine.
    • Fludarabine.
    • Pralatrexate.
    • Rituximab.
    • Vinblastine.
    • Vincristine.
    • Vinorelbine.

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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  10. 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.
  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.
  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.

Prevention and Management of Acute or Delayed Nausea and Vomiting (N&V)

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.[1,2,3,4]

Antiemetic agents are the most common intervention in the management of treatment-related 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 [7,8] 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, aprepitant, and dexamethasone is recommended prechemotherapy; lorazepam may also be used. Aprepitant and dexamethasone are recommended starting with chemotherapy for the prevention of delayed emesis.

For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT3 receptor antagonist and dexamethasone is 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, may 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 recommended.[7,8]

Antiemetic guidelines [7,8] 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.[9]

Studies have strongly suggested that patients experience more acute and delayed CINV than is perceived by practitioners.[9,10,11] One study suggested that patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea.[12] 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.[13]

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

Table 2. Antiemetic Recommendations by Emetic Risk Categoriesa
Emetic Risk Category ASCO Guidelines NCCN Guidelines
5-HT3 = 5-hydroxytryptamine-3; ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network.
a Adapted from Navari.[14]
b Order of listed antiemetics does not reflect preference.
High (>90%) risk Three-drug combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant is recommended prechemotherapy. Prechemotherapy, a 5-HT3 receptor antagonist (ondansetron, granisetron, dolasetron, or palonosetronb), dexamethasone (12 mg), and aprepitant (125 mg) are recommended, with or without lorazepam.
For patients receiving cisplatin and all other agents of high emetic risk, the two-drug combination of dexamethasone and aprepitant is recommended for prevention of delayed emesis continuing for several days after the day of chemotherapy. For patients receiving an anthracycline and cyclophosphamide, the three-drug combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant is recommended prechemotherapy; aprepitant plus dexamethasone is recommended on days 2 and 3 for prevention of delayed emesis. For prevention of delayed emesis, dexamethasone (8 mg) on days 2–4 plus aprepitant (80 mg) on days 2 and 3 is recommended, with or without lorazepam on days 2–4. If the patient receives 150 mg of fosaprepitant on the day of chemotherapy, then days 2 and 3 of aprepitant are not needed.
Moderate (30%–90%) risk   For patients receiving chemotherapies of moderate emetic risk (e.g., carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate), a 5-HT3 receptor antagonist (ondansetron, granisetron, dolasetron, or palonosetronb), dexamethasone (12 mg), and aprepitant (125 mg) are recommended, with or without lorazepam, prechemotherapy; for other patients, aprepitant is not recommended.
For patients receiving chemotherapies of moderate emetic risk, the two-drug combination of a 5-HT3 receptor antagonist and dexamethasone is recommended prechemotherapy; single-agent dexamethasone or a 5-HT3 receptor antagonist is recommended on days 2 and 3 for prevention of delayed emesis. For prevention of delayed emesis, dexamethasone (8 mg) or a 5-HT3 receptor antagonist on days 2–4 or, if used on day 1, aprepitant (80 mg) on days 2 and 3, with or without dexamethasone (8 mg) on days 2–4, is recommended, with or without lorazepam on days 2–4.
Low (10%–30%) risk Dexamethasone (8 mg) is recommended; no routine preventive use of antiemetics for delayed emesis recommended. Metoclopramide, with or without diphenhydramine; dexamethasone (12 mg); or prochlorperazine is recommended, with or without lorazepam.
Minimal (<10%) risk No antiemetic is administered routinely pre- or postchemotherapy. No routine prophylaxis; consider using antiemetics listed under primary prophylaxis as treatment.

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 (neurokinin-1 [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
Drug Category Medication Dose Available Route Comment Reference
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; CINV = chemotherapy-induced nausea and vomiting; EPS = extrapyramidal symptoms; FDA = U.S. Food and Drug Administration; IM = intramuscular; IV = intravenous; NK-1 = neurokinin-1; PO = oral; PR = rectal; qd = every day; SL = sublingual.
Phenothiazines Chlorpromazine 10–25 mg PO q4–6h PO, IM Prolongs QT interval [15,16][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 [15]
5–10 mg PO/IM/IV q6–8h
Promethazine 12.5–25 mg q4–6h PO, IM, IV, PR Vesicant; weak antiemetic [15][Level of evidence: IV]
Butyrophenones Haloperidol 1–4 mg q6h PO, IV, IM Used for treatment; rarely used for prophylaxis; prolongs QT interval [17][Level of evidence: III]
Droperidol 0.625–2.5 mg/dose IV Prolongs QT interval; used primarily for treatment [15,17][Level of evidence: III]
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; pretreat with diphenhydramine to prevent EPS; enhances gastric emptying [15]
Treatment of CINV: 10–40 mg PO q4–6h; 0.5 mg/kg PO q6h
Trimethobenzamide 300 mg PO q6–8h PO, IM Unavailable in United States [15,18][Level of evidence: II]
200 mg IM q6–8h
Serotonin (5-HT3) receptor antagonists Dolasetron 100 mg within 1 h prechemotherapy PO IV form withdrawn from market due to QTc prolongation [15]
Granisetron 1–2 mg PO or 10 µg/kg up to 1 mg IV within 1 h of chemotherapy IV, PO, topical Transdermal patch may be left in place ≤1 wk [15]
3.1 mg/24 h
Transdermal patch applied at least 24 h prechemotherapy
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; post-approval studies show 8 mg IV equivalent to larger doses [15,17][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
Palonosetron 0.25 mg IV or 0.5 mg PO 30 min prechemotherapy day 1 IV, PO   [15]
Substance P antagonists (NK-1 receptor antagonists) Aprepitant 125 mg prechemotherapy day 1, then 80 mg daily x2 d PO CYP3A4 enzyme inhibitor; CYP2C9 enzyme inducer [15]
Fosaprepitant 150 mg prechemotherapy day 1 IV CYP3A4 enzyme inhibitor; CYP2C9 enzyme inducer [15]
Netupitant (combined with palonosetron) Netupitant 300 mg/palonosetron 0.5 mg prechemotherapy day 1 PO CYP3A4 enzyme inhibitor [15]
Rolapitant 180 mg prechemotherapy day 1 PO FDA approved 2 Sept 2015 [15]
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. [15]
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 [17][Level of evidence: III]
Benzodiazepines Alprazolam 0.25–1 mg q6–8h PO Shortest half-life in drug class [15,19][Level of evidence: I]
Lorazepam 0.5–2 mg q6h PO, SL, IM, IV Most-commonly used in drug class [15]
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 [20][Level of evidence: I]
Treatment of breakthrough CINV: 10 mg PO daily x3 d [21][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   [15]
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 [15]
Cannabis No current data on dosing Inhaled, PO Currently, not enough data to recommendCannabisproducts for prevention/treatment of CINV [22][Level of evidence: IV]
Ginger 0.5–2 g/d prechemotherapy PO Current literature demonstrates conflicting efficacy results [23,24][Level of evidence: II]

Phenothiazines

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

The primary consideration in selecting phenothiazines are differences in their adverse effect profiles, which correlate with their structural classes. Generally, aliphatic phenothiazines (e.g., chlorpromazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine) are associated with less sedation but greater 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.[25,26,27,28,29][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.[30]

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.[31,32] Haloperidol is typically administered from 1 mg to 4 mg IM, IV, or orally, every 2 to 6 hours.[33] Results of a small, uncontrolled, open-label study showed some efficacy for haloperidol in palliative care patients.[34] Both agents may produce EPS, akathisia, hypotension, and sedation.

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.[35] Common side effects include the following:[36,37]

  • 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.[38][Level of evidence: II]. Subsequent studies have shown the effectiveness of olanzapine as a CINV antiemetic.[39,40][Level of evidence: II]. A large study [41][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 complete response (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.[20][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.[42,43]

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 by 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.[44,45,46]

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.[47] 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 nausea and vomiting.[18]

5-HT3 Receptor Antagonists

Four serotonin receptor antagonists—ondansetron, granisetron, dolasetron, and palonosetron—are available in the United States. Tropisetron, while not approved by the U.S. Food and Drug Administration (FDA), is available in other countries. 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.[48,49,50] 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.[51,52]; [53][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.[54]; [55][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.[9,56,57,58]

Ondansetron

Several studies have demonstrated that ondansetron produces an antiemetic response that equals or is superior to that of high doses of metoclopramide, but ondansetron has an improved toxicity profile, compared with that of dopaminergic antagonist agents.[59,60,61,62][Level of evidence: I][63,64] Ondansetron (0.15 mg/kg IV) is given 15 to 30 minutes before chemotherapy and repeated every 4 hours for two additional doses. A randomized trial of cisplatin found no difference between the 8-mg and 32-mg doses.[65] 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.[66] However, data reported to the 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.[67]

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.[68]

The major adverse effects of ondansetron include the following:[69]

  • 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.[70] 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.[71] A randomized, double-blind, placebo-controlled trial suggested that the addition of aprepitant, an NK-1 receptor antagonist, may mitigate N&V.[72,73][Level of evidence: I]

Granisetron

Granisetron has demonstrated efficacy in preventing and controlling N&V at a broad range of doses (e.g., 10–80 µg/kg and empirically, 3 mg per dose). In the United States, granisetron 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.[71,72,73,74][Level of evidence: I] Both granisetron formulations are given before chemotherapy, either as a single IV dose of 10 µg/kg (0.01 mg/kg) or as 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 N&V associated with moderately emetogenic chemotherapy.

Currently, granisetron injection 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. 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.[75]

The effectiveness of oral dolasetron in the prevention of CINV has been proven in a large randomized, double-blind, comparative trial of 399 patients.[76][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 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.[77][Level of evidence: I] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[78,79,80,81,82]

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.[54]; [55][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,[83][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 [84] 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.

Aprepitant/fosaprepitant

Clinical trials [85,86,87,88] 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 2–4 postchemotherapy; or standard therapy plus aprepitant prechemotherapy and on days 2 and 3.[89,90][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.[91][Level of evidence: I]

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.[92,93,94] 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.[95] 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.[96] 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.[96] Fosaprepitant is formulated with polysorbate 80, a solubilizing agent, which can cause rare but serious hypersensitivity reactions.[97,98]

Netupitant

Netupitant is a competitive antagonist to the NK-1 receptor that is marketed as an oral fixed-combination product containing 300 mg of netupitant and 0.5 mg of palonosetron. 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 in both highly and moderately emetogenic chemotherapy regimens.[99,100]

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.[101,102,103]

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 to moderately emetogenic chemotherapy but are more often used in antiemetic drug combinations.[104,105][Level of evidence: I][106]

Steroids are often 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).[107,108] 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.[105,109]

Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:[110,111,112]

  • 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).[113] As previously shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT3 –blocking agents.[110,114] 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.[115,116,117,118]

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.[110,111,112] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents; therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents.[119] 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.[120];[121][Level of evidence: I][122,123] Alprazolam has been shown to be effective when given in combination with metoclopramide and methylprednisolone.[19]

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).[124] 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.[125] Another product, Sativex, contains a combination of delta-9-THC and cannabidiol and is a buccal spray; it is under clinical investigation.[126,127]

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).[128,129,130,131,132] This group of studies demonstrated that cannabinoids were as effective for moderately emetogenic chemotherapy as dopaminergic antiemetics or were more effective than placebo.[124] Side effects included euphoria, dizziness, dysphoria, hallucinations, and hypotension.[124] Despite earlier reports of efficacy, in at least one study, patients did not significantly prefer nabilone because of the side effects.[128]

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.[133,134]

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.[135]

Refer to the PDQ summary on Cannabis and Cannabinoids for a broader discussion of the issues surrounding Cannabis use.

Ginger

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.[23]

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.[2,7,136,137] Evidence demonstrates benefit for the addition of an NK-1 antagonist to highly and moderately emetogenic multiday chemotherapy.[2,7,136,137] 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.[136,138] 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.[13,136]

Standard antiemetic prophylaxis includes a 5-HT3 antagonist given before the first chemotherapy dose each day of a multiday chemotherapy regimen.[2,7,136,137] 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.[81] 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).[139] Palonosetron was also studied with dexamethasone as prophylaxis for a 5-day cisplatin-based regimen for germ cell tumors.[13] 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.[74] 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.[140] 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.[141]

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.[95] 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.[142] 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.[143] 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.[143] This has led to the addition of NK-1 antagonists to the daily dosing of a serotonin antagonist plus dexamethasone.[143,144,145] Additional evidence is needed to determine optimal combinations as CR rates range as low as 30%.[145] 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.[146] Also, emesis is controlled to a much greater extent than is nausea, which continues to be challenging for many patients.[143,147] 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.[144]

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials for supportive and palliative care trials about nausea and vomiting therapy that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

  1. García Gómez J, Pérez López ME, García Mata J, et al.: SEOM clinical guidelines for the treatment of antiemetic prophylaxis in cancer patients receiving chemotherapy. Clin Transl Oncol 12 (11): 770-4, 2010.
  2. Basch E, Prestrud AA, Hesketh PJ, et al.: Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29 (31): 4189-98, 2011.
  3. Dupuis LL, Boodhan S, Holdsworth M, et al.: Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 60 (7): 1073-82, 2013.
  4. Dupuis LL, Robinson PD, Boodhan S, et al.: Guideline for the prevention and treatment of anticipatory nausea and vomiting due to chemotherapy in pediatric cancer patients. Pediatr Blood Cancer 61 (8): 1506-12, 2014.
  5. Hesketh PJ: Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology (Williston Park) 18 (10 Suppl 6): 9-14, 2004.
  6. Rudd JA, Andrews PLR: Mechanisms of acute, delayed, and anticipatory emesis induced by anticancer therapies. In: Hesketh PJ, ed.: Management of Nausea and Vomiting in Cancer and Cancer Treatment. Sudbury, Mass: Jones and Bartlett Publishers, Inc., 2005, pp 15-66.
  7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 2.2016. Fort Washington, Pa: National Comprehensive Cancer Network, 2016. Available online with free registration. Last accessed January 24, 2017.
  8. 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.
  9. Navari RM: Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting--two new agents. J Support Oncol 1 (2): 89-103, 2003 Jul-Aug.
  10. Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.
  11. Fabi A, Barduagni M, Lauro S, et al.: Is delayed chemotherapy-induced emesis well managed in oncological clinical practice? An observational study. Support Care Cancer 11 (3): 156-61, 2003.
  12. Colagiuri B, Roscoe JA, Morrow GR, et al.: How do patient expectancies, quality of life, and postchemotherapy nausea interrelate? Cancer 113 (3): 654-61, 2008.
  13. Einhorn LH, Brames MJ, Dreicer R, et al.: Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer 15 (11): 1293-300, 2007.
  14. Navari RM: Overview of the updated antiemetic guidelines for chemotherapy-induced nausea and vomiting. Community Oncology 4 (4 Suppl 1): 3-11, 2007..
  15. Lexicomp Online. Hudson, Ohio: Lexi-Comp, Inc., 2017. Available online with subscription. Last accessed January 24, 2017.
  16. Gez E, Brufman G, Kaufman B, et al.: Methylprednisolone and chlorpromazine in patients receiving cancer chemotherapy: a prospective non-randomized study. J Chemother 1 (2): 140-3, 1989.
  17. ASHP Therapeutic Guidelines on the Pharmacologic Management of Nausea and Vomiting in Adult and Pediatric Patients Receiving Chemotherapy or Radiation Therapy or Undergoing Surgery. Am J Health Syst Pharm 56 (8): 729-64, 1999.
  18. Hurley JD, Eshelman FN: Trimethobenzamide HCl in the treatment of nausea and vomiting associated with antineoplastic chemotherapy. J Clin Pharmacol 20 (5-6 Pt 1): 352-6, 1980 May-Jun.
  19. Mori K, Saito Y, Tominaga K: Antiemetic efficacy of alprazolam in the combination of metoclopramide plus methylprednisolone. Double-blind randomized crossover study in patients with cisplatin-induced emesis. Am J Clin Oncol 16 (4): 338-41, 1993.
  20. Navari RM, Qin R, Ruddy KJ, et al.: Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 375 (2): 134-42, 2016.
  21. Navari RM, Nagy CK, Gray SE: The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 21 (6): 1655-63, 2013.
  22. Todaro B: Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw 10 (4): 487-92, 2012.
  23. Ryan JL, Heckler CE, Roscoe JA, et al.: Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients. Support Care Cancer 20 (7): 1479-89, 2012.
  24. Marx WM, Teleni L, McCarthy AL, et al.: Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting: a systematic literature review. Nutr Rev 71 (4): 245-54, 2013.
  25. Olver IN, Webster LK, Bishop JF, et al.: A dose finding study of prochlorperazine as an antiemetic for cancer chemotherapy. Eur J Cancer Clin Oncol 25 (10): 1457-61, 1989.
  26. Carr BI, Bertrand M, Browning S, et al.: A comparison of the antiemetic efficacy of prochlorperazine and metoclopramide for the treatment of cisplatin-induced emesis: a prospective, randomized, double-blind study. J Clin Oncol 3 (8): 1127-32, 1985.
  27. Olver IN, Wolf M, Laidlaw C, et al.: A randomised double-blind study of high-dose intravenous prochlorperazine versus high-dose metoclopramide as antiemetics for cancer chemotherapy. Eur J Cancer 28A (11): 1798-802, 1992.
  28. Levinson DF, Simpson GM: Neuroleptic-induced extrapyramidal symptoms with fever. Heterogeneity of the 'neuroleptic malignant syndrome'. Arch Gen Psychiatry 43 (9): 839-48, 1986.
  29. Wampler G: The pharmacology and clinical effectiveness of phenothiazines and related drugs for managing chemotherapy-induced emesis. Drugs 25 (Suppl 1): 35-51, 1983.
  30. American Geriatrics Society 2012 Beers Criteria Update Expert Panel: American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 60 (4): 616-31, 2012.
  31. Mason BA, Dambra J, Grossman B, et al.: Effective control of cisplatin-induced nausea using high-dose steroids and droperidol. Cancer Treat Rep 66 (2): 243-5, 1982.
  32. Kelley SL, Braun TJ, Meyer TJ, et al.: Trial of droperidol as an antiemetic in cisplatin chemotherapy. Cancer Treat Rep 70 (4): 469-72, 1986.
  33. Plotkin DA, Plotkin D, Okun R: Haloperidol in the treatment of nausea and vomiting due to cytotoxic drug administration. Curr Ther Res Clin Exp 15 (9): 599-602, 1973.
  34. Hardy JR, O'Shea A, White C, et al.: The efficacy of haloperidol in the management of nausea and vomiting in patients with cancer. J Pain Symptom Manage 40 (1): 111-6, 2010.
  35. Bymaster FP, Falcone JF, Bauzon D, et al.: Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine. Eur J Pharmacol 430 (2-3): 341-9, 2001.
  36. ZYPREXA (olanzapine): highlights of prescribing information. Indianapolis, Ind: Eli Lilly and Company, 2016. Available online. Last accessed January 24, 2017.
  37. Hocking CM, Kichenadasse G: Olanzapine for chemotherapy-induced nausea and vomiting: a systematic review. Support Care Cancer 22 (4): 1143-51, 2014.
  38. Passik SD, Lundberg J, Kirsh KL, et al.: A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage 23 (6): 526-32, 2002.
  39. Navari RM, Einhorn LH, Passik SD, et al.: A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer 13 (7): 529-34, 2005.
  40. Navari RM, Einhorn LH, Loehrer PJ Sr, et al.: A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer 15 (11): 1285-91, 2007.
  41. Tan L, Liu J, Liu X, et al.: Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting. J Exp Clin Cancer Res 28: 131, 2009.
  42. Navari RM, Gray SE, Kerr AC: Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol 9 (5): 188-95, 2011 Sep-Oct.
  43. Mizukami N, Yamauchi M, Koike K, et al.: Olanzapine for the prevention of chemotherapy-induced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: a randomized, double-blind, placebo-controlled study. J Pain Symptom Manage 47 (3): 542-50, 2014.
  44. Navari RM: Comparison of intermittent versus continuous infusion metoclopramide in control of acute nausea induced by cisplatin chemotherapy. J Clin Oncol 7 (7): 943-6, 1989.
  45. Agostinucci WA, Gannon RH, Golub GR, et al.: Continuous i.v. infusion versus multiple bolus doses of metoclopramide for prevention of cisplatin-induced emesis. Clin Pharm 7 (6): 454-7, 1988.
  46. Kris MG, Gralla RJ, Tyson LB, et al.: Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients. Cancer 55 (3): 527-34, 1985.
  47. Kris MG, Tyson LB, Gralla RJ, et al.: Extrapyramidal reactions with high-dose metoclopramide. N Engl J Med 309 (7): 433-4, 1983.
  48. Hsu ES: A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics. Am J Ther 17 (5): 476-86, 2010 Sep-Oct.
  49. Trammel M, Roederer M, Patel J, et al.: Does pharmacogenomics account for variability in control of acute chemotherapy-induced nausea and vomiting with 5-hydroxytryptamine type 3 receptor antagonists? Curr Oncol Rep 15 (3): 276-85, 2013.
  50. Hatoum HT, Lin SJ, Buchner D, et al.: Comparative clinical effectiveness of various 5-HT3 RA antiemetic regimens on chemotherapy-induced nausea and vomiting associated with hospital and emergency department visits in real world practice. Support Care Cancer 20 (5): 941-9, 2012.
  51. Aogi K, Sakai H, Yoshizawa H, et al.: A phase III open-label study to assess safety and efficacy of palonosetron for preventing chemotherapy-induced nausea and vomiting (CINV) in repeated cycles of emetogenic chemotherapy. Support Care Cancer 20 (7): 1507-14, 2012.
  52. Hesketh PJ: Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting. Cancer Invest 18 (2): 163-73, 2000.
  53. Navari R, Gandara D, Hesketh P, et al.: Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. The Granisetron Study Group. J Clin Oncol 13 (5): 1242-8, 1995.
  54. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al.: Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer 98 (11): 2473-82, 2003.
  55. Gralla R, Lichinitser M, Van Der Vegt S, et al.: Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol 14 (10): 1570-7, 2003.
  56. Boccia R, Grunberg S, Franco-Gonzales E, et al.: Efficacy of oral palonosetron compared to intravenous palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: a phase 3 trial. Support Care Cancer 21 (5): 1453-60, 2013.
  57. Hickok JT, Roscoe JA, Morrow GR, et al.: 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol 6 (10): 765-72, 2005.
  58. Kris MG: Why do we need another antiemetic? Just ask. J Clin Oncol 21 (22): 4077-80, 2003.
  59. Tyers MB: Pharmacology and preclinical antiemetic properties of ondansetron. Semin Oncol 19 (4 Suppl 10): 1-8, 1992.
  60. Kaasa S, Kvaløy S, Dicato MA, et al.: A comparison of ondansetron with metoclopramide in the prophylaxis of chemotherapy-induced nausea and vomiting: a randomized, double-blind study. International Emesis Study Group. Eur J Cancer 26 (3): 311-4, 1990.
  61. Hainsworth J, Harvey W, Pendergrass K, et al.: A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy. J Clin Oncol 9 (5): 721-8, 1991.
  62. De Mulder PH, Seynaeve C, Vermorken JB, et al.: Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Ann Intern Med 113 (11): 834-40, 1990.
  63. Marty M, Pouillart P, Scholl S, et al.: Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 322 (12): 816-21, 1990.
  64. Hesketh PJ: Comparative trials of ondansetron versus metoclopramide in the prevention of acute cisplatin-induced emesis. Semin Oncol 19 (4 Suppl 10): 33-40, 1992.
  65. Pectasides D, Mylonakis A, Varthalitis J, et al.: Comparison of two different doses of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced emesis. Oncology 54 (1): 1-6, 1997 Jan-Feb.
  66. Hasler SB, Hirt A, Ridolfi Luethy A, et al.: Safety of ondansetron loading doses in children with cancer. Support Care Cancer 16 (5): 469-75, 2008.
  67. U.S. Food and Drug Administration: FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). Silver Spring, Md: U.S. Food and Drug Administration, 2012. Available online. Last accessed January 12, 2017.
  68. Beck TM, Hesketh PJ, Madajewicz S, et al.: Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 10 (12): 1969-75, 1992.
  69. Finn AL: Toxicity and side effects of ondansetron. Semin Oncol 19 (4 Suppl 10): 53-60, 1992.
  70. Coates AS, Childs A, Cox K, et al.: Severe vascular adverse effects with thrombocytopenia and renal failure following emetogenic chemotherapy and ondansetron. Ann Oncol 3 (9): 719-22, 1992.
  71. Ruff P, Paska W, Goedhals L, et al.: Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. The Ondansetron and Granisetron Emesis Study Group. Oncology 51 (1): 113-8, 1994 Jan-Feb.
  72. Jantunen IT, Muhonen TT, Kataja VV, et al.: 5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy--a randomised study. Eur J Cancer 29A (12): 1669-72, 1993.
  73. Gebbia V, Cannata G, Testa A, et al.: Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and vomiting. Results of a prospective randomized trial. Cancer 74 (7): 1945-52, 1994.
  74. Boccia RV, Gordan LN, Clark G, et al.: Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer 19 (10): 1609-17, 2011.
  75. U.S. Food and Drug Administration: FDA Drug Safety Communication: Abnormal heart rhythms associated with use of Anzemet (dolasetron mesylate). Silver Spring, Md: U.S. Food and Drug Administration, 2010. Available online. Last accessed January 24, 2017.
  76. Fauser AA, Duclos B, Chemaissani A, et al.: Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. European Dolasetron Comparative Study Group. Eur J Cancer 32A (9): 1523-9, 1996.
  77. Eisenberg P, MacKintosh FR, Ritch P, et al.: Efficacy, safety and pharmacokinetics of palonosetron in patients receiving highly emetogenic cisplatin-based chemotherapy: a dose-ranging clinical study. Ann Oncol 15 (2): 330-7, 2004.
  78. Tricco AC, Soobiah C, Antony J, et al.: Safety of serotonin (5-HT3) receptor antagonists in patients undergoing surgery and chemotherapy: protocol for a systematic review and network meta-analysis. Syst Rev 2: 46, 2013.
  79. Faria C, Li X, Nagl N, et al.: Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis. Am Health Drug Benefits 7 (1): 50-8, 2014.
  80. Schwartzberg L, Barbour SY, Morrow GR, et al.: Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV). Support Care Cancer 22 (2): 469-77, 2014.
  81. Affronti ML, Bubalo J: Palonosetron in the management of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy. Cancer Manag Res 6: 329-37, 2014.
  82. Navari RM: Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy. Cancer Manag Res 1: 167-76, 2009.
  83. Aapro MS, Grunberg SM, Manikhas GM, et al.: A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 17 (9): 1441-9, 2006.
  84. Navari RM: Palonosetron: a second-generation 5-hydroxytryptamine receptor antagonist. Future Oncol 2 (5): 591-602, 2006.
  85. Humphreys S, Pellissier J, Jones A: Cost-effectiveness of an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer in the UK. Cancer Manag Res 5: 215-24, 2013.
  86. Warr DG, Street JC, Carides AD: Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: analysis of phase 3 trial of aprepitant in patients receiving adriamycin-cyclophosphamide-based chemotherapy. Support Care Cancer 19 (6): 807-13, 2011.
  87. Hesketh PJ, Aapro M, Street JC, et al.: Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: analysis of two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy. Support Care Cancer 18 (9): 1171-7, 2010.
  88. Hu W, Fang J, Nie J, et al.: Addition of aprepitant improves protection against cisplatin-induced emesis when a conventional anti-emetic regimen fails. Cancer Chemother Pharmacol 73 (6): 1129-36, 2014.
  89. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al.: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 97 (12): 3090-8, 2003.
  90. Hesketh PJ, Grunberg SM, Gralla RJ, et al.: The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol 21 (22): 4112-9, 2003.
  91. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al.: Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 17 (6): 1000-6, 2006.
  92. Warr DG, Hesketh PJ, Gralla RJ, et al.: Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23 (12): 2822-30, 2005.
  93. Rapoport BL, Jordan K, Boice JA, et al.: Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer 18 (4): 423-31, 2010.
  94. Aapro MS, Schmoll HJ, Jahn F, et al.: Review of the efficacy of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in a range of tumor types. Cancer Treat Rev 39 (1): 113-7, 2013.
  95. Albany C, Brames MJ, Fausel C, et al.: Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a hoosier oncology group study. J Clin Oncol 30 (32): 3998-4003, 2012.
  96. Grunberg S, Chua D, Maru A, et al.: Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol--EASE. J Clin Oncol 29 (11): 1495-501, 2011.
  97. EMEND (Fosaprepitant Dimeglumine) for Injection, for Intravenous Use. Kenilworth, NJ: Merck & Co., Inc., 2016. Available online. Last accessed January 24, 2017.
  98. Shelley WB, Talanin N, Shelley ED: Polysorbate 80 hypersensitivity. Lancet 345 (8960): 1312-3, 1995.
  99. Hesketh PJ, Rossi G, Rizzi G, et al.: Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol 25 (7): 1340-6, 2014.
  100. Aapro M, Rugo H, Rossi G, et al.: A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 25 (7): 1328-33, 2014.
  101. Schwartzberg LS, Modiano MR, Rapoport BL, et al.: Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol 16 (9): 1071-8, 2015.
  102. Rapoport BL, Chasen MR, Gridelli C, et al.: Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol 16 (9): 1079-89, 2015.
  103. VARUBI (Rolapitant) Tablets, for Oral Use. Waltham, Mass: TESARO, Inc., 2015. Available online. Last accessed January 24, 2017.
  104. Bishop JF, Matthews JP, Wolf MM, et al.: A randomised trial of dexamethasone, lorazepam and prochlorperazine for emesis in patients receiving chemotherapy. Eur J Cancer 28 (1): 47-50, 1992.
  105. Chiara S, Campora E, Lionetto R, et al.: Methylprednisolone for the control of CMF-induced emesis. Am J Clin Oncol 10 (3): 264-7, 1987.
  106. Parry H, Martin K: Single-dose i.v. dexamethasone--an effective anti-emetic in cancer chemotherapy. Cancer Chemother Pharmacol 28 (3): 231-2, 1991.
  107. Cassileth PA, Lusk EJ, Torri S, et al.: Antiemetic efficacy of high-dose dexamethasone in induction therapy in acute nonlymphocytic leukemia. Ann Intern Med 100 (5): 701-2, 1984.
  108. Aapro MS, Plezia PM, Alberts DS, et al.: Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone versus high-dose metoclopramide. J Clin Oncol 2 (5): 466-71, 1984.
  109. Schallier D, Van Belle S, De Greve J, et al.: Methylprednisolone as an antiemetic drug. A randomised double blind study. Cancer Chemother Pharmacol 14 (3): 235-7, 1985.
  110. Kris MG, Gralla RJ, Clark RA, et al.: Consecutive dose-finding trials adding lorazepam to the combination of metoclopramide plus dexamethasone: improved subjective effectiveness over the combination of diphenhydramine plus metoclopramide plus dexamethasone. Cancer Treat Rep 69 (11): 1257-62, 1985.
  111. Greenberg DB, Surman OS, Clarke J, et al.: Alprazolam for phobic nausea and vomiting related to cancer chemotherapy. Cancer Treat Rep 71 (5): 549-50, 1987.
  112. 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.
  113. Münstedt K, Borces D, Bohlmann MK, et al.: Glucocorticoid administration in antiemetic therapy: is it safe? Cancer 101 (7): 1696-702, 2004.
  114. Roila F, Tonato M, Cognetti F, et al.: Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 9 (4): 675-8, 1991.
  115. Zaglama NE, Rosenblum SL, Sartiano GP, et al.: Single, high-dose intravenous dexamethasone as an antiemetic in cancer chemotherapy. Oncology 43 (1): 27-32, 1986.
  116. Klygis LM: Dexamethasone-induced perineal irritation in head injury. Am J Emerg Med 10 (3): 268, 1992.
  117. More on dexamethasone-induced perineal irritation. N Engl J Med 314 (25): 1643-4, 1986.
  118. Baharav E, Harpaz D, Mittelman M, et al.: Dexamethasone-induced perineal irritation. N Engl J Med 314 (8): 515-6, 1986.
  119. Triozzi PL, Goldstein D, Laszlo J: Contributions of benzodiazepines to cancer therapy. Cancer Invest 6 (1): 103-11, 1988.
  120. Laszlo J, Clark RA, Hanson DC, et al.: Lorazepam in cancer patients treated with cisplatin: a drug having antiemetic, amnesic, and anxiolytic effects. J Clin Oncol 3 (6): 864-9, 1985.
  121. Bishop JF, Olver IN, Wolf MM, et al.: Lorazepam: a randomized, double-blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and prochlorperazine. J Clin Oncol 2 (6): 691-5, 1984.
  122. Henry DW, Burwinkle JW, Klutman NE: Determination of sedative and amnestic doses of lorazepam in children. Clin Pharm 10 (8): 625-9, 1991.
  123. van Hoff J, Olszewski D: Lorazepam for the control of chemotherapy-related nausea and vomiting in children. J Pediatr 113 (1 Pt 1): 146-9, 1988.
  124. Ben Amar M: Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 105 (1-2): 1-25, 2006.
  125. Davis MP: Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin Investig Drugs 17 (1): 85-95, 2008.
  126. Duran M, Pérez E, Abanades S, et al.: Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol 70 (5): 656-63, 2010.
  127. Machado Rocha FC, Stéfano SC, De Cássia Haiek R, et al.: Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl) 17 (5): 431-43, 2008.
  128. Ahmedzai S, Carlyle DL, Calder IT, et al.: Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer 48 (5): 657-63, 1983.
  129. Chan HS, Correia JA, MacLeod SM: Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 79 (6): 946-52, 1987.
  130. Johansson R, Kilkku P, Groenroos M: A double-blind, controlled trial of nabilone vs. prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat Rev 9 (Suppl B): 25-33, 1982.
  131. Niiranen A, Mattson K: A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. Am J Clin Oncol 8 (4): 336-40, 1985.
  132. Tramèr MR, Carroll D, Campbell FA, et al.: Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323 (7303): 16-21, 2001.
  133. Meiri E, Jhangiani H, Vredenburgh JJ, et al.: Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin 23 (3): 533-43, 2007.
  134. Strasser F, Luftner D, Possinger K, et al.: Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol 24 (21): 3394-400, 2006.
  135. Coffman KL: The debate about marijuana usage in transplant candidates: recent medical evidence on marijuana health effects. Curr Opin Organ Transplant 13 (2): 189-95, 2008.
  136. Roila F, Herrstedt J, Aapro M, et al.: Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 21 (Suppl 5): v232-43, 2010.
  137. Einhorn LH, Rapoport B, Koeller J, et al.: Antiemetic therapy for multiple-day chemotherapy and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support Care Cancer 13 (2): 112-6, 2005.
  138. Baltzer L, Pisters KM, Kris MG, et al.: High dose ondansetron (OND) plus dexamethasone (DEX) for the prevention of nausea and vomiting with multiple day cisplatin chemotherapy. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-1607, 462, 1993.
  139. Lorusso V, Giampaglia M, Petrucelli L, et al.: Antiemetic efficacy of single-dose palonosetron and dexamethasone in patients receiving multiple cycles of multiple day-based chemotherapy. Support Care Cancer 20 (12): 3241-6, 2012.
  140. Jordan K, Kinitz I, Voigt W, et al.: Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer 45 (7): 1184-7, 2009.
  141. Olver IN, Grimison P, Chatfield M, et al.: Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Support Care Cancer 21 (6): 1561-8, 2013.
  142. Adra N, Albany C, Brames MJ, et al.: Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in patients with germ cell tumors undergoing 5-day cisplatin-based chemotherapy: a Hoosier Cancer Research Network study. Support Care Cancer 24 (7): 2837-42, 2016.
  143. Stiff PJ, Fox-Geiman MP, Kiley K, et al.: Prevention of nausea and vomiting associated with stem cell transplant: results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow Transplant 19 (1): 49-55.e1, 2013.
  144. Schmitt T, Goldschmidt H, Neben K, et al.: Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial. J Clin Oncol 32 (30): 3413-20, 2014.
  145. Sakurai M, Mori T, Kato J, et al.: Efficacy of aprepitant in preventing nausea and vomiting due to high-dose melphalan-based conditioning for allogeneic hematopoietic stem cell transplantation. Int J Hematol 99 (4): 457-62, 2014.
  146. Bubalo JS, Cherala G, McCune JS, et al.: Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J Clin Pharmacol 52 (4): 586-94, 2012.
  147. Yeh SP, Lo WC, Hsieh CY, et al.: Palonosetron and dexamethasone for the prevention of nausea and vomiting in patients receiving allogeneic hematopoietic stem cell transplantation. Support Care Cancer 22 (5): 1199-206, 2014.

Nonpharmacologic Management of Nausea and Vomiting (N&V)

Nonpharmacologic strategies are also used to manage N&V. These include the following:

  • Dietary alterations. (Refer to the Nausea subsection of the Nutritional Suggestions for Symptom Management section in 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.)

Radiation-Induced Nausea and Vomiting (RINV)

Introduction

Radiation therapy (RT) is an important cause of nausea and vomiting (N&V) in the cancer patient. Observational studies suggest an 80% overall cumulative incidence rate of some degree of N&V among patients undergoing RT.[1] Risk factors for developing N&V are known. RINV worsens quality of life, leading to treatment delays and cancelled appointments, compromising cancer control.[2,3]

Epidemiology

Two large prospective observational studies provide information on the frequency of RINV and antiemetic measures. The Italian Group for Antiemetic Research in Radiotherapy analyzed the incidence of RINV in 1,020 patients receiving various kinds of radiation therapy.[4] Overall, nausea, vomiting, or both were reported by 28% of patients. The median time to the first episode of vomiting was 3 days. Antiemetic drugs were administered to 17% of the patients, including 12% treated prophylactically and 5% given rescue therapy. In a second cohort of 368 patients receiving RT, the overall incidence rate for nausea was 39% and for vomiting, 7%.[5] Nausea was more frequent in those receiving RT to the lower abdomen or pelvis (66%) compared with patients receiving RT to the head-and-neck area (48%). Antiemetics during RT are underprescribed.[6]

Pathophysiology

The pathophysiology of RINV is incompletely understood. Serotonin, substance P, and dopamine are neurotransmitters involved in radiation-induced emesis.[7] RINV bears a close similarity to chemotherapy-induced N&V (CINV). The effectiveness of serotonin antagonists in RINV supports a role for serotonin in radiation-induced emesis.[7] Substance P antagonists have not been used in RINV as extensively as they are in CINV. Preclinical work suggests a role for substance P in RINV.[8] Substance P antagonists are only beginning to be studied for RINV. Substance P may play a role in prolonged N&V after the administration of RT.

Risk Stratification

Radiation site, volume, fractionation schedule, and single and total dose determine the incidence and severity of RINV. The most important factor appears to be the radiation field. Table 4 shows risk categories suggested by the Multinational Association of Supportive Care in Cancer (MASCC), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO).[9] Risk of nausea is not considered in the classification.[10] The risk of N&V for a patient being treated with RT depends on multiple other factors in addition to the emetogenicity of the specific RT regimen. Patient-specific factors include the simultaneous administration of chemotherapy, age, gender, alcohol consumption, anxiety, and previous experience of RINV or CINV.[3]

Table 4. Risk Classification for RINV
Emetogenic Potential Risk of Emesis Without Prophylaxis Location
HBI = hemibody irradiation; RINV = radiation-induced nausea and vomiting; TBI = total body irradiation; TNI = total nodal irradiation; UBI = upper-body irradiation.
High >90% TBI, TNI
Moderate 60%–90% Upper-abdominal irradiation, HBI, UBI
Low 30%–60% Cranium (all), craniospinal, head and neck, lower thorax region, pelvis
Minimal <30% Breast, extremities

Treatment

The body of literature describing treatments for RINV is much smaller than that for CINV.[11] Most of the studies done were for patients with moderate- to high-risk features for RINV.

Antiemetic therapy: prevention and treatment of N&V

Several studies show the superiority of serotonin antagonists for the prophylaxis of RINV.[12,13,14,15,16,17] Ondansetron, dolasetron, and tropisetron showed superiority over placebo or metoclopramide. Dosing of the serotonin antagonists have been single-dose pretreatment or for consecutive days (up to 5–7 days total). Most studies have been conducted in patients at moderate to high risk of RINV.

Recommended dosing is ondansetron 8 mg, regardless of schedule given.[3] Dolasetron dosing has ranged from 0.3 to 1.2 mg/kg intravenously. Granisetron dosing is 2 mg orally per day.[3] A recent meta-analysis covering nine clinical trials showed differing rates of control when emesis versus nausea is considered. Compared with placebo, fewer patients had residual emesis (40% vs. 57%; relative risk [RR], 0.7), and fewer patients required rescue medication (6.5% vs. 36%; RR, 0.18).[18] The control of nausea seems to be more difficult. Most patients developed RT-induced nausea despite treatment (70% vs. 83% with placebo; RR, 0.84).[19] In summary, these trials show that patients receiving upper-abdomen irradiation have a greater benefit using 5-hydroxytryptamine-3 (5-HT3) receptor antagonists than metoclopramide, phenothiazines, or placebo to control RINV.[12,13,14,15,16,17]

The adverse effects of 5-HT3 receptor antagonists are generally mild, consisting mainly of headache, constipation, and asthenia.[20] Randomized trials in RINV have utilized four different 5-HT3 receptor antagonists (ondansetron, granisetron, dolasetron, and tropisetron). There are no data comparing those different 5-HT3 receptor antagonists, and there is no consensus on optimal dosing for RINV.[21] A systematic review including 25 randomized and nonrandomized trials revealed that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT. Optimal duration and timing of 5-HT3 use before, during, and after the administration of RT needs to be determined.[22] With regard to palonosetron, the newest 5-HT3 receptor antagonist, there are no fully published studies on the appropriate dosing and frequency in the RINV setting, in contrast to the CINV setting. However, the updated ASCO guideline suggests that dosing every second or third day may be appropriate for this agent.[23]

Corticosteroids

Corticosteroids are an attractive therapeutic antiemetic option because of their widespread availability and low cost. For short-term use, the side effects are few and do not outweigh the benefit of these agents. One randomized trial showed that dexamethasone was significantly more effective than placebo in patients receiving RT to the upper abdomen.[24] Combining corticosteroids with a 5-HT3 receptor antagonist was assessed in a well-designed randomized trial in which a 5-day course of dexamethasone plus ondansetron was compared with ondansetron plus placebo in 211 patients who received RT to the upper abdomen.[25] During the first 5 days, there was a statistically nonsignificant trend toward complete control of nausea (50% vs. 38% with placebo) and vomiting (78% vs. 71%), which was the primary objective of the trial. The effects of dexamethasone extended beyond the initial 5-day period, and significantly more patients had complete control of emesis over the entire course of RT (23% vs. 12% with placebo), a secondary objective of the trial. The trial demonstrates that the addition of dexamethasone has a modest effect on RINV and is potentially a useful addition to a 5-HT3 receptor antagonist in this setting.[25]

Neurokinin-1 (NK-1) receptor antagonists

NK-1 receptor antagonists have an established role in the management of CINV; however, no studies have evaluated the impact of this drug class solely on the risk of RINV. Although preclinical data indicate that RINV is mediated in part by substance P,[8] recommendation of these agents is premature. Therefore, NK-1 receptor antagonists are not reflected in the antiemetic guidelines for RINV.[3] Data from a small clinical trial (N = 59) presented at the 2011 MASCC meeting provides a first hint that NK-1 receptor antagonists in combination with 5-HT3 receptor antagonists and dexamethasone proved to be advantageous in the prophylaxis of acute and delayed nausea during simultaneous chemoradiotherapy, compared with the standard antiemetic treatment. More patients on the emetic prophylaxis containing NK-1 receptor antagonists reached a complete response.[26]

Other agents

Older, less-specific antiemetic drugs such as prochlorperazine, metoclopramide, and cannabinoids have shown limited efficacy in the prevention or treatment of RINV, although they may have a role in treating patients with milder symptoms and as rescue agents.[27]

Duration of prophylaxis

The appropriate duration of antiemetic prophylaxis for patients receiving fractionated RT is not clear. There have been no randomized trials using 5-HT3 receptor antagonists that compared a 5-day course of treatment with a more protracted course.[7] A systematic review that included 25 randomized and nonrandomized trials revealed that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT.[22] Despite a lack of evidence, the current National Comprehensive Cancer Network guidelines recommend that the decision about whether to continue antiemetic prophylaxis beyond the first week should be based on an assessment of the risk of emesis and relevant individual factors.[28]

Rescue Therapy

The benefit of 5-HT3 receptor antagonists once nausea or vomiting occurs has been suggested in all studies, but there are no trials specifically in this setting.[29] The emerging role of olanzapine in breakthrough emesis in patients with CINV has not been studied in RINV.[30]

Guidelines and Patient Management

For patients at high risk of developing RINV, prophylaxis with a 5-HT3 receptor antagonist is recommended in the clinical practice guidelines from both MASCC and ASCO. On the basis of results from patients receiving highly emetogenic chemotherapy, the addition of dexamethasone to the 5-HT3 receptor antagonist is suggested. The antiemetic clinical practice guidelines from both MASCC and ASCO recommend that patients receiving moderately emetogenic RT be administered prophylaxis with a 5-HT3 receptor antagonist, with or without a short course of dexamethasone.[7] There are no fully published comparative clinical trials on the use of NK-1 receptor antagonists in preventing RINV; therefore, its use cannot be recommended.

Antiemetic dosing suggestions for the prevention of RINV are summarized in Table 5.

Table 5. Antiemetic Dosing for Radiation Therapya
Drug Category Antiemetic Dose Comment Reference
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; IV = intravenously; PO = by mouth; prn = as needed; RT = radiation therapy; TBI = total-body irradiation; tid = 3 times a day.
a Adapted from Roila et al.[31]and Basch et al.[32]
Serotonin (5-HT3) receptor antagonists Granisetron 2 mg PO daily   [16][Level of evidence: I]
Ondansetron 1 mg or 0.01 mg/kg IV daily bid-tid with TBI [21][Level of evidence: I]
Palonosetron 0.25 mg IV or 0.5 mg PO Not studied in RT; no data available on frequency of administration [32][Level of evidence: IV]
Dolasetron 100 mg PO only   [13][Level of evidence: I]
Corticosteroids Dexamethasone 4 mg PO or IV During fractions 1–5 [25][Level of evidence: I]
Dopamine receptor antagonists Metoclopramide 20 mg PO prn during minimal-emetic-risk RT; inferior to 5-HT3 receptor antagonists [21][Level of evidence: I]
Prochlorperazine 10 mg PO or IV prn during minimal-emetic-risk RT [32][Level of evidence: IV]

References:

  1. Dennis K, Maranzano E, De Angelis C, et al.: Radiotherapy-induced nausea and vomiting. Expert Rev Pharmacoecon Outcomes Res 11 (6): 685-92, 2011.
  2. Maranzano E: Radiation-induced emesis: a problem with many open questions. Tumori 87 (4): 213-8, 2001 Jul-Aug.
  3. Feyer PC, Maranzano E, Molassiotis A, et al.: Radiotherapy-induced nausea and vomiting (RINV): MASCC/ESMO guideline for antiemetics in radiotherapy: update 2009. Support Care Cancer 19 (Suppl 1): S5-14, 2011.
  4. Maranzano E, De Angelis V, Pergolizzi S, et al.: A prospective observational trial on emesis in radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres. Radiother Oncol 94 (1): 36-41, 2010.
  5. Enblom A, Bergius Axelsson B, Steineck G, et al.: One third of patients with radiotherapy-induced nausea consider their antiemetic treatment insufficient. Support Care Cancer 17 (1): 23-32, 2009.
  6. Horiot JC: Prophylaxis versus treatment: is there a better way to manage radiotherapy-induced nausea and vomiting? Int J Radiat Oncol Biol Phys 60 (4): 1018-25, 2004.
  7. Feyer P, Jahn F, Jordan K: Radiation induced nausea and vomiting. Eur J Pharmacol 722: 165-71, 2014.
  8. Yamamoto K, Nohara K, Furuya T, et al.: Ondansetron, dexamethasone and an NK1 antagonist block radiation sickness in mice. Pharmacol Biochem Behav 82 (1): 24-9, 2005.
  9. Hesketh PJ, Bohlke K, Lyman GH, et al.: Antiemetics: American Society of Clinical Oncology Focused Guideline Update. J Clin Oncol 34 (4): 381-6, 2016.
  10. Feyer PCh, Maranzano E, Molassiotis A, et al.: Radiotherapy-induced nausea and vomiting (RINV): antiemetic guidelines. Support Care Cancer 13 (2): 122-8, 2005.
  11. Chow E, Meyer RM, Ding K, et al.: Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial. Lancet Oncol 16 (15): 1463-72, 2015.
  12. Aass N, Håtun DE, Thoresen M, et al.: Prophylactic use of tropisetron or metoclopramide during adjuvant abdominal radiotherapy of seminoma stage I: a randomised, open trial in 23 patients. Radiother Oncol 45 (2): 125-8, 1997.
  13. Bey P, Wilkinson PM, Resbeut M, et al.: A double-blind, placebo-controlled trial of i.v. dolasetron mesilate in the prevention of radiotherapy-induced nausea and vomiting in cancer patients. Support Care Cancer 4 (5): 378-83, 1996.
  14. Volk A, Kersting S, Konopke R, et al.: Surgical therapy of intrapancreatic metastasis from renal cell carcinoma. Pancreatology 9 (4): 392-7, 2009.
  15. Franzén L, Nyman J, Hagberg H, et al.: A randomised placebo controlled study with ondansetron in patients undergoing fractionated radiotherapy. Ann Oncol 7 (6): 587-92, 1996.
  16. Lanciano R, Sherman DM, Michalski J, et al.: The efficacy and safety of once-daily Kytril (granisetron hydrochloride) tablets in the prophylaxis of nausea and emesis following fractionated upper abdominal radiotherapy. Cancer Invest 19 (8): 763-72, 2001.
  17. Priestman TJ, Dunn J, Brada M, et al.: Final results of the Royal College of Radiologists' trial comparing two different radiotherapy schedules in the treatment of cerebral metastases. Clin Oncol (R Coll Radiol) 8 (5): 308-15, 1996.
  18. Priestman TJ, Roberts JT, Upadhyaya BK: A prospective randomized double-blind trial comparing ondansetron versus prochlorperazine for the prevention of nausea and vomiting in patients undergoing fractionated radiotherapy. Clin Oncol (R Coll Radiol) 5 (6): 358-63, 1993.
  19. Chow E, Zeng L, Salvo N, et al.: Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol) 24 (2): 112-24, 2012.
  20. Goodin S, Cunningham R: 5-HT(3)-receptor antagonists for the treatment of nausea and vomiting: a reappraisal of their side-effect profile. Oncologist 7 (5): 424-36, 2002.
  21. Salvo N, Doble B, Khan L, et al.: Prophylaxis of radiation-induced nausea and vomiting using 5-hydroxytryptamine-3 serotonin receptor antagonists: a systematic review of randomized trials. Int J Radiat Oncol Biol Phys 82 (1): 408-17, 2012.
  22. Dennis K, Nguyen J, Presutti R, et al.: Prophylaxis of radiotherapy-induced nausea and vomiting in the palliative treatment of bone metastases. Support Care Cancer 20 (8): 1673-8, 2012.
  23. Basch E, Prestrud AA, Hesketh PJ, et al.: Antiemetic Use in Oncology: Updated Guideline Recommendations from ASCO. Am Soc Clin Oncol Educ Book : 532-40, 2012.
  24. Kirkbride P, Bezjak A, Pater J, et al.: Dexamethasone for the prophylaxis of radiation-induced emesis: a National Cancer Institute of Canada Clinical Trials Group phase III study. J Clin Oncol 18 (9): 1960-6, 2000.
  25. Wong RK, Paul N, Ding K, et al.: 5-hydroxytryptamine-3 receptor antagonist with or without short-course dexamethasone in the prophylaxis of radiation induced emesis: a placebo-controlled randomized trial of the National Cancer Institute of Canada Clinical Trials Group (SC19). J Clin Oncol 24 (21): 3458-64, 2006.
  26. Jahn F, Riesner A, Jahn P, et al.: Addition of the Neurokinin-1-Receptor Antagonist (RA) Aprepitant to a 5-Hydroxytryptamine-RA and Dexamethasone in the Prophylaxis of Nausea and Vomiting Due to Radiation Therapy With Concomitant Cisplatin. Int J Radiat Oncol Biol Phys 92 (5): 1101-7, 2015.
  27. Roila F, Herrstedt J, Gralla RJ, et al.: Prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: guideline update and results of the Perugia consensus conference. Support Care Cancer 19 (Suppl 1): S63-5, 2011.
  28. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 2.2016. Fort Washington, Pa: National Comprehensive Cancer Network, 2016. Available online with free registration. Last accessed January 24, 2017.
  29. Mystakidou K, Katsouda E, Linou A, et al.: Prophylactic tropisetron versus rescue tropisetron in fractionated radiotherapy to moderate or high emetogenic areas: a prospective randomized open label study in cancer patients. Med Oncol 23 (2): 251-62, 2006.
  30. Navari RM, Nagy CK, Gray SE: The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 21 (6): 1655-63, 2013.
  31. Roila F, Molassiotis A, Herrstedt J, et al.: 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol 27 (suppl 5): v119-v133, 2016.
  32. Basch E, Prestrud AA, Hesketh PJ, et al.: Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29 (31): 4189-98, 2011.

Pediatric Chemotherapy-Induced Acute Nausea and Vomiting (N&V)

Published Pediatric Antiemetic Guidelines for Acute N&V

Chemotherapy-induced N&V (CINV) is an important problem in the pediatric population. As in adults, nausea in children is more of a problem than vomiting. Nausea was identified by parents of children receiving active antineoplastic therapy in Ontario as the fourth most prevalent and bothersome treatment-related symptom in their children.[1] Current approaches to the selection of appropriate and effective measures to prevent CINV are based on an accurate description of the potential of antineoplastic therapies to cause N&V. Current recommendations are based on published guidelines.[2] These recommendations include patients aged 1 month to 18 years. Published recommendations are based on patients naïve to antineoplastic therapy who are about to receive their first course of antineoplastic therapy. Recommendations focus on the prevention of acute CINV (i.e., within 24 hours of administration of an antineoplastic agent).

Guidelines recommend that optimal control of acute CINV be defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for CINV prevention, and no nausea-related change in the child's usual appetite and diet. This level of CINV control is to be achieved on each day that antineoplastic therapy is administered and for 24 hours after administration of the last agent in the antineoplastic therapy cycle.

Emetic Risk

In children receiving antineoplastic agents who were not given antiemetic prophylaxis or who were given prophylaxis known to be ineffective, expected rates of complete CINV control were as follows: high emetic risk, less than 10%; moderate emetic risk, 10% to less than 30%; low emetic risk, 30% to less than 90%; and minimal emetic risk, more than 90%.[2] The expected rate of complete CINV control in children receiving modern antiemetic prophylaxis (5-hydroxytryptamine-3 [5-HT3] antagonist with or without dexamethasone) is more than 70% to 80%.[2] Each chemotherapy agent carries an inherent risk of causing emesis, which is the first issue to be considered in the assessment of an individual's risk when planning treatment with chemotherapy. Refer to Table 3 for more information about the prevention of acute or delayed CINV.

Antiemetic Prophylaxis

Highly emetogenic chemotherapy

Guidelines [2,3] recommend that children aged 12 years and older who are receiving antineoplastic agents of high emetic risk that are not known or suspected to interact with aprepitant receive aprepitant plus a 5-HT3 antagonist plus dexamethasone. Children who cannot receive dexamethasone should receive a 5-HT3 antagonist plus aprepitant. Children who cannot receive aprepitant should receive a 5-HT3 antagonist plus dexamethasone.

Moderately emetogenic chemotherapy

Children receiving antineoplastic agents of moderate emetogenicity should receive ondansetron, granisetron, or palonosetron plus dexamethasone. Children who cannot receive dexamethasone should receive 5-HT3 antagonist plus aprepitant.[3]

Low emetogenic chemotherapy

Children receiving antineoplastic agents of low emetogenicity should receive a 5-HT3 antagonist.[3]

Minimal emetogenic potential

Children receiving antineoplastic agents of low emetogenicity should receive no routine prophylaxis.[3]

Other Antiemetic Modalities

Current consensus is that acupuncture, acupressure, guided imagery, music therapy, progressive muscle relaxation, and psychoeducational support and information may be effective in children receiving antineoplastic agents.[2] Virtual reality may convey benefit. Other recommendations (low level of evidence) include eating smaller, more-frequent meals; reducing food aromas and other stimuli with strong odors; avoiding foods that are spicy, fatty, or highly salty; taking antiemetics before meals so that the effect is present during and after meals; and using measures and foods (e.g., "comfort foods") that helped to minimize nausea in the past. Despite a lack of strong evidence, most experts feel that these recommendations are unlikely to result in undesirable effects or to adversely affect quality of life and may convey benefit.

Antiemetics

Prophylaxis with a 5-HT3 antagonist alone leads to poor CINV control in patients receiving antineoplastic agents of moderate and high emetic risk. A synthesis of the three studies that evaluated alternative antiemetic agents (chlorpromazine and metoclopramide) in children receiving highly emetogenic chemotherapy observed a complete CINV control rate of 9% (95% confidence interval: 0, 20).[2] When corticosteroids are contraindicated, it is recommended that nabilone or chlorpromazine be administered together with ondansetron or granisetron to children receiving highly emetogenic chemotherapy. Metoclopramide is a third option for children receiving moderately emetogenic chemotherapy. It is also recommended that corticosteroids be combined with a serotonin antagonist for patients receiving highly and moderately emetogenic chemotherapy.[4]

Antiemetic dosing suggestions for pediatric patients are summarized in Table 6.

Table 6. Pediatric Antiemetic Dosing
Drug Category Medication Dose Available Route Comment Reference
5-HT3 = 5-hydroxytryptamine-3; bid = twice a day; BSA = body surface area; EPS = extrapyramidal symptoms; IM = intramuscular; IV = intravenous; NK-1 = neurokinin-1; PO = oral; PR = rectal; prn = as needed; qd = every day; SL = sublingual; tid = 3 times a day.
a Palonosetron prescribing information lists the pediatric maximum dose at 1.5 mg.
Phenothiazines Chlorpromazine 0.5 mg/kg/dose q6h; may increase to 1 mg/kg/dose q6h; maximum dose: 50 mg IV Prolongs QTc interval; use with 5-HT3 antagonist when corticosteroid contraindicated; dose adjustments based on efficacy and sedation [5];[2][Level of evidence: IV];[6][Level of evidence: I]
Prochlorperazine 9–13 kg: 2.5 mg PO qd–bid; maximum dose: 7.5 mg/d PO, IM, IV Less sedation, but increased risk of EPS [5];[7][Level of evidence: I]
13–18 kg: 2.5 mg PO bid–tid; maximum dose: 10 mg/d
18–39 kg: 2.5 mg tid or 5 mg bid; maximum dose: 15 mg/d
Promethazine Age >2 y: 0.25–1 mg/kg/dose q4–6h; maximum dose: 25 mg PO, IM, IV, PR Vesicant [5]
Substituted benzamides Metoclopramide Moderately emetogenic chemotherapy: 1 mg/kg/dose IV once prechemotherapy, then 0.0375 mg/kg/dose PO q6h PO, IM, IV EPS associated with higher doses; pretreat with benztropine or diphenhydramine to prevent EPS; enhances gastric emptying [5];[8][Level of evidence: I]
Serotonin (5-HT3) receptor antagonists Granisetron 40 μg/kg IV daily; 40 μg/kg PO q12h; maximum: 1 mg/dose IV, PO   [9][Level of evidence: I]
Ondansetron Age 0–<12 y: 0.15 mg/kg/dose (5 mg/m2 /dose) prechemotherapy, then q8h for highly emetogenic or q12h for moderately emetogenic chemotherapy PO, IV Avoid IV doses >16 mg due to QTc prolongation; age >12 y: follow adult dosing [5];[2][Level of evidence: IV]
Low emetogenic chemotherapy: 0.3 mg/kg/dose (10 mg/m2 /dose) once prechemotherapy
Maximum PO dose: 24 mg; maximum IV dose: 16 mg
Palonosetron Age 1 mo–17 y: 20 μg/kg; maximum dose: 0.75 mga IV, PO Due to pediatric half-life of 30 h, administered q2–3d during multiday chemotherapy [2][Level of evidence: I]; Maximum dose:[10]
Substance P antagonists (NK-1 receptor antagonists) Aprepitant Capsule: Age >12 y: 125 mg prechemotherapy day 1, then 80 mg qd x2 d PO CYP3A4 enzyme inhibitor; CYP2C9 enzyme inducer [11][Level of evidence: I]
Suspension: Age 6 mo–12 y (and >6 kg): 3 mg/kg prechemotherapy day 1, then 2 mg/kg qd x2 d Suspension: Maximum dose day 1: 125 mg; maximum dose days 2–3: 80 mg
Fosaprepitant Age 13–17 y: 150 mg IV CYP3A4 enzyme inhibitor; CYP2C9 enzyme inducer [12][Level of evidence: III]
Corticosteroids Dexamethasone Highly emetogenic chemotherapy: 6 mg/m2 /dose q6h PO, IV May be omitted in some brain tumor, osteosarcoma, and carcinoma protocols due to fear of reducing cytotoxic effects of chemotherapy [5];[2][Level of evidence: IV]
Moderately emetogenic chemotherapy: BSA ≤0.6 m2: 2 mg q12h Combined with 5-HT3 receptor antagonist
BSA >0.6 m2: 4 mg q12h When given with aprepitant or fosaprepitant, reduce dose by 50%
Maximum: 20 mg/dose Most effective for delayed nausea
Methylprednisolone 4–10 mg/kg/dose PO, IV Given with 5-HT3 antagonist [13,14][Level of evidence: I]
Benzodiazepines Lorazepam Anticipatory: 0.02–0.05 mg/kg/dose (maximum: 2 mg/dose) once at bedtime the night before chemotherapy and once prechemotherapy PO, SL, IM, IV Most-commonly used drug in class [5]
Breakthrough: 0.02–0.05 mg/kg/dose IV (maximum: 2 mg) q6h prn [15][Level of evidence: IV]
Atypical antipsychotics Olanzapine 0.1–0.14 mg/kg/dose qd; maximum: 10 mg PO   [16][Level of evidence: III]
Other pharmacologic agents Dronabinol Age 6–18 y: 2.1 mg/m2 1–3 h prechemotherapy PO Single-institution experience only; benefit of appetite stimulant properties [17][Level of evidence: III]
Nabilone Age >4 y: PO May be continued up to 48 h postchemotherapy; has not been compared with 5-HT3 antagonist with or without corticosteroid; use with 5-HT3 antagonist when corticosteroid contraindicated [18][Level of evidence: I];[7]
<18 kg: 0.5 mg q12h
18–30 kg: 1 mg q12h
>30 kg: 1 mg q8–12h
Maximum dose: 0.06 mg/kg/d

Multiagent single-day chemotherapy regimens

Experience in pediatrics and guidelines recommend basing the emetogenicity of combination antineoplastic regimens on that of the agent of highest emetic risk of many combinations.[19] The emetogenicity of the antineoplastic combinations in the following list appears to be higher than would be appreciated by assessment of the emetic risk of the individual agents.[20]

High Level of Emetic Risk (>90% Frequency of Emesis in Absence of Prophylaxis)

  • Cyclophosphamide + anthracycline.
  • Cyclophosphamide + etoposide.
  • Cytarabine (150–200 mg/m2) + daunorubicin.
  • Cytarabine (300 mg/m2) + etoposide.
  • Cytarabine (300 mg/m2) + teniposide.
  • Doxorubicin + ifosfamide.
  • Doxorubicin + methotrexate (5 g/m2).
  • Etoposide + ifosfamide.

References:

  1. Dupuis LL, Milne-Wren C, Cassidy M, et al.: Symptom assessment in children receiving cancer therapy: the parents' perspective. Support Care Cancer 18 (3): 281-99, 2010.
  2. Dupuis LL, Boodhan S, Holdsworth M, et al.: Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 60 (7): 1073-82, 2013.
  3. Dupuis LL, Sung L, Molassiotis A, et al.: 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children. Support Care Cancer 25 (1): 323-331, 2017.
  4. White L, Daly SA, McKenna CJ, et al.: A comparison of oral ondansetron syrup or intravenous ondansetron loading dose regimens given in combination with dexamethasone for the prevention of nausea and emesis in pediatric and adolescent patients receiving moderately/highly emetogenic chemotherapy. Pediatr Hematol Oncol 17 (6): 445-55, 2000.
  5. Lexicomp Online. Hudson, Ohio: Lexi-Comp, Inc., 2017. Available online with subscription. Last accessed January 24, 2017.
  6. Relling MV, Mulhern RK, Fairclough D, et al.: Chlorpromazine with and without lorazepam as antiemetic therapy in children receiving uniform chemotherapy. J Pediatr 123 (5): 811-6, 1993.
  7. Chan HS, Correia JA, MacLeod SM: Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics 79 (6): 946-52, 1987.
  8. Köseoglu V, Kürekçi AE, Sarici U, et al.: Comparison of the efficacy and side-effects of ondansetron and metoclopramide-diphenhydramine administered to control nausea and vomiting in children treated with antineoplastic chemotherapy: a prospective randomized study. Eur J Pediatr 157 (10): 806-10, 1998.
  9. Berrak SG, Ozdemir N, Bakirci N, et al.: A double-blind, crossover, randomized dose-comparison trial of granisetron for the prevention of acute and delayed nausea and emesis in children receiving moderately emetogenic carboplatin-based chemotherapy. Support Care Cancer 15 (10): 1163-8, 2007.
  10. Kadota R, Shen V, Messinger Y: Safety, pharmacokinetics, and efficacy of palonosetron in pediatric patients: a multicenter, stratified, double-blind, phase 3, randomized study. [Abstract] J Clin Oncol 25 (18 suppl): A-9570, 2007.
  11. Kang HJ, Loftus S, Taylor A, et al.: Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 16 (4): 385-94, 2015.
  12. Siddiqui MA, Ghaznawi HI: Some observations on intestinal parasites in Hajis visiting Saudi Arabia, during 1983 G (1403 H.) Pilgrimage. J Egypt Soc Parasitol 15 (2): 705-12, 1985.
  13. Small BE, Holdsworth MT, Raisch DW, et al.: Survey ranking of emetogenic control in children receiving chemotherapy. J Pediatr Hematol Oncol 22 (2): 125-32, 2000 Mar-Apr.
  14. Hirota T, Honjo T, Kuroda R, et al.: [Antiemetic efficacy of granisetron in pediatric cancer treatment--(2). Comparison of granisetron and granisetron plus methylprednisolone as antiemetic prophylaxis]. Gan To Kagaku Ryoho 20 (15): 2369-73, 1993.
  15. Dupuis LL, Nathan PC: Options for the prevention and management of acute chemotherapy-induced nausea and vomiting in children. Paediatr Drugs 5 (9): 597-613, 2003.
  16. Flank J, Thackray J, Nielson D, et al.: Olanzapine for treatment and prevention of acute chemotherapy-induced vomiting in children: a retrospective, multi-center review. Pediatr Blood Cancer 62 (3): 496-501, 2015.
  17. Elder JJ, Knoderer HM: Characterization of Dronabinol Usage in a Pediatric Oncology Population. J Pediatr Pharmacol Ther 20 (6): 462-7, 2015 Nov-Dec.
  18. Dalzell AM, Bartlett H, Lilleyman JS: Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child 61 (5): 502-5, 1986.
  19. Dupuis LL, Boodhan S, Sung L, et al.: Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 57 (2): 191-8, 2011.
  20. Holdsworth MT, Raisch DW, Frost J: Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer 106 (4): 931-40, 2006.

Pediatric Delayed Nausea and Vomiting (N&V)

In adults, delayed N&V is well documented, and strategies exist to control it. Delayed N&V remains a significant problem despite major improvements in the control of acute N&V and nausea immediately following the administration of chemotherapy. The nature and prevalence of delayed N&V in children after administration of antineoplastic agents have not been well described.[1] Additionally, most pediatric chemotherapy regimens give multiple days of chemotherapy, making the onset and duration of risk for delayed versus acute N&V unclear.

Work in the area of chemotherapy-induced N&V (CINV) in children has been limited in part by the lack of assessment tools and the subjective nature of nausea. In the pediatric population, vomiting is more easily recognizable and measurable than is nausea.[1] Difficulties in assessing nausea in young children may contribute to the common perception that young children experience CINV less frequently than do older children. In addition, caregivers may have a higher tolerance for vomiting in young children and may miss detecting nausea.[1] In view of these limitations, studies often use dietary intake to assess the extent of nausea.

Several investigators have attempted to determine the prevalence of delayed N&V in the pediatric population. Early work suggested a low incidence of delayed N&V.[2] In a large study, the nature and prevalence of delayed CINV in children was assessed.[1] Nausea was self-assessed daily using a numeric scale reflecting the effect of nausea on activities and a faces scale for children aged 3 to 6 years. Diet was also assessed daily. Results showed a 33% incidence of delayed vomiting in patients receiving antineoplastic agents (cyclophosphamide, cisplatin, or carboplatin) and an 11% incidence in those who received other antineoplastic agents. No antiemetics were given on 412 (79%) of 522 study days; nevertheless, 381 (93%) of the 412 study days on which patients did not receive antiemetic support during the delayed phase were completely free from vomiting. Antiemetics were most often given as single agents (ondansetron, on 54 study days; dimenhydrinate, on 17 study days; dexamethasone, on 6 study days). Diet was not affected. The authors concluded that antineoplastic-induced delayed N&V may be less prevalent in children than in adults.[1] The high percentage of children not experiencing delayed vomiting may reflect a lack of significant emetogenic potential among many of the regimens in the study; in 100 of 174 chemotherapy cycles, no antiemetics were administered. In addition, there was no characterization of antiemetic response among moderate and severe chemotherapy regimens.

Another study evaluated the incidence of delayed N&V in pediatric patients receiving moderately and highly emetogenic chemotherapy and also receiving premedications in the form of ondansetron alone or with dexamethasone, depending on a treatment's emetogenic potential.[3] In this study, investigators measured nausea severity and duration, vomiting severity, the number of vomiting episodes, interference with daily activities by the nausea or vomiting, and assessment of appetite. The authors found that delayed N&V occurred with both moderately and highly emetogenic regimens. The severity of N&V varied between the moderately emetogenic and highly emetogenic chemotherapy regimens. The investigators also found that toddlers had better antiemetic control than did older children, which may be the result of anxiety differences between the age groups. The reasons for greater complete control in the toddler patient population are unclear but are consistent with the authors' previous study of nausea and vomiting control rates in children.[4] Anxiety and patient perception may be important contributors to N&V in older children; the authors found a relationship between control of acute N&V and the occurrence of delayed N&V.

Another study suggests a higher incidence of delayed N&V.[5] In a sample of pediatric cancer patients (N = 40) receiving chemotherapy, N&V was measured from the child's perspective using the Adapted Rhodes Index of Nausea and Vomiting for Pediatrics; from the primary caregiver's perspective using the Adapted Rhodes Index of Nausea and Vomiting for Parents; and among their nurses using the National Cancer Institute Nausea and Vomiting Grading Criteria. The highest frequency of nausea occurred in the delayed period, with 60% of patients (n = 24) having reported delayed nausea. The authors concluded that chemotherapy-induced N&V occurred throughout the chemotherapy course, with delayed N&V occurring most frequently and with greater severity and distress. Delayed N&V in the pediatric population requires further study.

Because well-designed studies on the prevention of delayed N&V in children are not available, no formal recommendation is possible. In the absence of such data, current consensus is to treat children in a manner similar to adults, with appropriately adjusted doses.[6]

References:

  1. Dupuis LL, Lau R, Greenberg ML: Delayed nausea and vomiting in children receiving antineoplastics. Med Pediatr Oncol 37 (2): 115-21, 2001.
  2. Foot AB, Hayes C: Audit of guidelines for effective control of chemotherapy and radiotherapy induced emesis. Arch Dis Child 71 (5): 475-80, 1994.
  3. Holdsworth MT, Raisch DW, Frost J: Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer 106 (4): 931-40, 2006.
  4. Small BE, Holdsworth MT, Raisch DW, et al.: Survey ranking of emetogenic control in children receiving chemotherapy. J Pediatr Hematol Oncol 22 (2): 125-32, 2000 Mar-Apr.
  5. Rodgers C, Kollar D, Taylor O, et al.: Nausea and vomiting perspectives among children receiving moderate to highly emetogenic chemotherapy treatment. Cancer Nurs 35 (3): 203-10, 2012 May-Jun.
  6. Dupuis LL, Sung L, Molassiotis A, et al.: 2016 updated MASCC/ESMO consensus recommendations: Prevention of acute chemotherapy-induced nausea and vomiting in children. Support Care Cancer 25 (1): 323-331, 2017.

Pediatric Anticipatory Nausea and Vomiting (ANV)

Cancer patients who have received chemotherapy may experience nausea and vomiting (N&V) when anticipating chemotherapy. Differences in methodology, timing, and assessment instruments and a focus on nausea or vomiting but not both has led to difficulties in capturing the actual prevalence of ANV in children. Small study sample sizes preclude capturing the actual frequency of ANV in the pediatric population. Accurate prevalence is also prevented by the use of parent or caregiver proxy reports of nausea and the use of nonvalidated nausea assessment tools.

When ANV was evaluated longitudinally in patients receiving 5-hydroxytryptamine-3 (5-HT3) antagonists and corticosteroids as antiemetic agents, approximately one-third of adults experienced ANV, while anticipatory vomiting was reported in 6% to 11%.[1] A single group of investigators has evaluated ANV in children in the pre–5-HT3 antagonist era. The study reported anticipatory nausea in 23 (29%) of 80 children and anticipatory vomiting in 16 (20%) of 80 children who had received 11 cycles of antineoplastic therapy, on average, before evaluation.[2] In the post–5-HT3 era, the reported prevalence of anticipatory nausea in children has ranged from 0% to 59%.[3] Similar to observations in adult patients, the reported prevalence of anticipatory nausea was always higher than that of anticipatory vomiting, with one exception: one study reported an equivalent prevalence (5 [26%] of 19 patients) for anticipatory nausea and anticipatory vomiting.[4]

This section focuses on the management of ANV in children aged 1 month to 18 years who are receiving antineoplastic medication. Optimal control of ANV is defined as no vomiting, no retching, no nausea, no use of antiemetic agents other than those given for the prevention or treatment of chemotherapy-induced N&V (CINV), and no nausea-related change in the child's usual appetite and diet. This level of ANV control is to be achieved during the 24 hours before administration of the first antineoplastic agent of the upcoming planned antineoplastic cycle.

Approaches to Prevent ANV in Children

ANV appears to be a conditioned response to CINV experienced in the acute phase (24 hours after administration of chemotherapy) and delayed phase (more than 24 hours after and within 7 days of administration of chemotherapy).[3] The anxiety and distress attendant to CINV reinforce the conditioned response.[3] It follows, therefore, that a higher rate of complete acute and delayed CINV control would result in lower rates of ANV. Adherence to evidence-based guideline recommendations regarding CINV prevention has been shown to substantially improve complete acute CINV control.[5]

Given that ANV appears to be a conditioned response, optimization of acute and delayed CINV control may help minimize exposure to the negative stimuli required for conditioning to occur. Consensus recommendations are that antiemetic interventions be based on published guidelines used for the prevention of acute CINV in children receiving antineoplastic agents,[6] including antineoplastic agent–naïve patients. Once antineoplastic therapy has been initiated, the selection of antiemetic interventions should be informed by evidence-based guidelines and tailored on the basis of the extent of CINV control experienced by the patient and any adverse effects associated with antiemetic agents.

Interventions to Control ANV

Hypnosis

Hypnosis has been defined as an intervention that "provides suggestions for changes in sensation, perception, cognition, affect, mood, or behavior."[7] Two trials evaluated the role of hypnosis in controlling ANV in children. One study recruited 54 children aged 5 to 17 years who had reported experiencing anticipatory nausea, anticipatory vomiting, or both in a previous study and who were about to receive at least two identical antineoplastic treatment courses.[8] On average, children were 15.8 months (range, 0.5–118 months) from their cancer diagnosis at the time of the study. The control group had received antineoplastic therapy for much longer than the other two groups (29.5 months vs. 8 or 11.5 months).

Although it is not possible to precisely ascertain the emetogenicity of the antineoplastic therapy that the children received, it appears that most received highly emetogenic treatment, as assessed by current classifications of chemotherapy emetogenicity. The antiemetic agents received for prophylaxis were not reported, but children's antiemetic regimens were unchanged during the trial. The severity of N&V was assessed through semistructured interviews. Children were randomly assigned to receive one of three possible interventions: hypnosis training (imagination-focused therapy), active cognitive distraction (relaxation), or contact with a therapist (control). The authors reported a significant improvement in complete control of anticipatory vomiting in the group who received hypnosis training (12 [57%] of 21 patients at baseline vs. 18 [86%] of 21 patients after hypnosis training; P < .05). Complete control of anticipatory nausea increased from 5 (24%) of 21 patients at baseline to 8 (38%) of 21 patients after hypnosis training.[8]

Another study evaluated hypnosis as a means of preventing ANV in 20 children aged 6 to 18 years who were naïve to chemotherapy.[9] Controls were matched for age (±3 years) and the emetogenicity of their antineoplastic treatment. Insufficient information is available to determine the emetogenicity of the antineoplastic regimens. Children randomly assigned to receive hypnosis did not receive antiemetic prophylaxis but did receive antiemetic agents as needed. Children in the control group received standard antiemetic prophylaxis for 4 to 6 hours after antineoplastic therapy. Ondansetron was given to more children in the control group (7 of 10 patients) than in the hypnosis group (3 of 10 patients).

Children randomly assigned to receive hypnosis were taught self-hypnosis during the initial antineoplastic treatment; children in the control group spent equivalent time in conversation with a therapist. ANV was assessed by means of a daily structured interview with the child. The presence of ANV was assessed at 1 to 2 months, and at 4 to 6 months after diagnosis. At the time of first assessment of ANV, children who had been taught self-hypnosis reported significantly less anticipatory nausea than did the control group, although the incidence was not reported. The rate of anticipatory vomiting was identical in each group (1 of 10 patients). By the time of the second assessment, there was no difference between the groups in the rate of anticipatory nausea. The rate of anticipatory vomiting between the groups was also similar (hypnosis, 0 of 10 patients vs. control, 2 of 10 patients).[9]

Pharmacological interventions

Studies of pharmacologic interventions for ANV have been conducted only in adults and are limited to benzodiazepines. Because patients who experience ANV have been observed to be more anxious than patients who do not experience ANV,[10] anxiolytics have been studied. Studies in adults (two randomized trials) have evaluated the contribution of benzodiazepines as a treatment for ANV.[11,12] Adult cancer patients received placebo or lorazepam 2 mg by mouth the night before antineoplastic treatment, the morning of treatment, and at bedtime for the next 5 days over 180 antineoplastic treatment courses containing cisplatin.[11] Patients also received metoclopramide 2 mg/kg per dose, clemastine, and dexamethasone for antiemetic prophylaxis. At the time of randomization, approximately two-thirds of patients were naïve to antineoplastic agents. ANV was defined as nausea, vomiting, or both that occurred within 12 hours before antineoplastic therapy or 1 hour after the start of antineoplastic therapy. A significantly higher proportion of treatments in which lorazepam was given were associated with complete ANV control, compared with the control group (52% vs. 32%; P < .05). Few adverse effects were attributed to lorazepam; mild sedation occurred in 76% of the patients who received lorazepam and 32% of the control patients.

Women with breast cancer that is naïve to antineoplastic treatment were enrolled in a double-blind placebo-controlled trial comparing the incidence of ANV after relaxation training and either alprazolam (29 patients) or placebo (28 patients). Alprazolam 0.25 mg or placebo was given twice daily by mouth for 6 to 12 months. Triazolam was also given as needed to patients in both study arms to manage insomnia. The proportion of patients who experienced complete control of anticipatory nausea and anticipatory vomiting before the fourth antineoplastic treatment was similar in both study arms (26% vs. 25% and 4% vs. 0%, respectively). Diazepam 5 mg twice daily was given to 29 adult cancer patients with ANV for 3 days before each of four consecutive antineoplastic treatment courses.[12] Thirteen patients (45%) experienced complete ANV control at some time over the four antineoplastic treatment courses.

Conclusions

While the improvement in complete control of ANV provided by psychological interventions such as hypnosis or systematic desensitization may not be dramatic, these interventions may convey benefit to individual patients with minimal risk. For this reason, one guideline development panel recommends that interventions be offered to age-appropriate patients who experience ANV where the expertise and resources exist to deliver them.[6]

Despite the lack of evidence to support the use of benzodiazepines for the treatment of ANV in children, guidelines recommend using lorazepam for ANV in children, based on clinical experience.[13] The recommended initial lorazepam dose was based on current pediatric dosing recommendations, with the usual adult dose as the maximum dose.[14] This dose should be titrated to the needs of each child, with dose lowering recommended for excessive sedation. Guidelines also recommend that dosing be of short duration.[14]

References:

  1. Morrow GR, Roscoe JA, Hynes HE, et al.: Progress in reducing anticipatory nausea and vomiting: a study of community practice. Support Care Cancer 6 (1): 46-50, 1998.
  2. Dolgin MJ, Katz ER, McGinty K, et al.: Anticipatory nausea and vomiting in pediatric cancer patients. Pediatrics 75 (3): 547-52, 1985.
  3. Tyc VL, Mulhern RK, Bieberich AA: Anticipatory nausea and vomiting in pediatric cancer patients: an analysis of conditioning and coping variables. J Dev Behav Pediatr 18 (1): 27-33, 1997.
  4. Stockhorst U, Spennes-Saleh S, Körholz D, et al.: Anticipatory symptoms and anticipatory immune responses in pediatric cancer patients receiving chemotherapy: features of a classically conditioned response? Brain Behav Immun 14 (3): 198-218, 2000.
  5. Aapro M, Molassiotis A, Dicato M, et al.: The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol 23 (8): 1986-92, 2012.
  6. Dupuis LL, Boodhan S, Holdsworth M, et al.: Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 60 (7): 1073-82, 2013.
  7. Montgomery GH, Schnur JB, Kravits K: Hypnosis for cancer care: over 200 years young. CA Cancer J Clin 63 (1): 31-44, 2013.
  8. Zeltzer LK, Dolgin MJ, LeBaron S, et al.: A randomized, controlled study of behavioral intervention for chemotherapy distress in children with cancer. Pediatrics 88 (1): 34-42, 1991.
  9. Jacknow DS, Tschann JM, Link MP, et al.: Hypnosis in the prevention of chemotherapy-related nausea and vomiting in children: a prospective study. J Dev Behav Pediatr 15 (4): 258-64, 1994.
  10. Andrykowski MA: The role of anxiety in the development of anticipatory nausea in cancer chemotherapy: a review and synthesis. Psychosom Med 52 (4): 458-75, 1990 Jul-Aug.
  11. Malik IA, Khan WA, Qazilbash M, et al.: Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol 18 (2): 170-5, 1995.
  12. Razavi D, Delvaux N, Farvacques C, et al.: Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of alprazolam. J Clin Oncol 11 (7): 1384-90, 1993.
  13. van Hoff J, Olszewski D: Lorazepam for the control of chemotherapy-related nausea and vomiting in children. J Pediatr 113 (1 Pt 1): 146-9, 1988.
  14. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Antiemesis. Version 2.2016. Fort Washington, Pa: National Comprehensive Cancer Network, 2016. Available online with free registration. Last accessed January 24, 2017.

Changes to This Summary (03 / 14 / 2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was renamed from Nausea and Vomiting.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the prevention and control of treatment-related nausea and vomiting in cancer patients. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Treatment-Related Nausea and Vomiting are:

  • Joseph Bubalo, PharmD, BCPS, BCOP (Oregon Health and Science University Hospital)
  • Lillian M. Nail, PhD, RN, FAAN, CNS (Oregon Health & Science University Cancer Institute)
  • Eric E. Prommer, MD (UCLA School of Medicine)
  • Megan Reimann, PharmD, BCOP (Indiana University Simon Cancer Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Treatment-Related Nausea and Vomiting. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389491]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2017-03-14