Health Care Costs

Severe N&V may result in prolonged hospitalizations, inability to continue usual activities, need for additional support, and depression, producing greater effects on health care costs. One review of 12 published studies [1] found that despite the high costs associated with prophylaxis against CINV, the direct cost of care was higher for patients who did not receive adequate CINV prophylaxis. Indirect costs related to lost work hours were also higher for patients with uncontrolled CINV. Another study examined 178 patients receiving highly or moderately emetogenic chemotherapy for their first chemotherapy course.[2] Despite prophylaxis, 61% still experienced CINV. Higher direct and indirect health care costs and lower Functional Living Index—Emesis (FLIE) scores for quality of life were seen in patients who failed prophylaxis. One group of investigators looked at the Premier Perspective database to study 19,139 patients, all of whom received prophylaxis. In those with uncontrolled CINV, the overall mean additional costs were $5,299 per episode.[3]

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.

References

1. Carlotto A, Hogsett VL, Maiorini EM, et al.: The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. Pharmacoeconomics 31 (9): 753-66, 2013. [PubMed: 23963867]
2. Haiderali A, Menditto L, Good M, et al.: Impact on daily functioning and indirect/direct costs associated with chemotherapy-induced nausea and vomiting (CINV) in a U.S. population. Support Care Cancer 19 (6): 843-51, 2011. [PubMed: 20532923]
3. Burke TA, Wisniewski T, Ernst FR: Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Support Care Cancer 19 (1): 131-40, 2011. [PubMed: 20101417]

References

1. Wickham R: Evolving treatment paradigms for chemotherapy-induced nausea and vomiting. Cancer Control 19 (2 Suppl): 3-9, 2012. [PubMed: 22488022]
2. Navari RM: Antiemetic control: toward a new standard of care for emetogenic chemotherapy. Expert Opin Pharmacother 10 (4): 629-44, 2009. [PubMed: 19284365]
3. Cefalo MG, Ruggiero A, Maurizi P, et al.: Pharmacological management of chemotherapy-induced nausea and vomiting in children with cancer. J Chemother 21 (6): 605-10, 2009. [PubMed: 20071282]
4. Darmani NA, Crim JL, Janoyan JJ, et al.: A re-evaluation of the neurotransmitter basis of chemotherapy-induced immediate and delayed vomiting: evidence from the least shrew. Brain Res 1248: 40-58, 2009. [PubMed: 19022231]

Classifications

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

• Acute N&V: N&V experienced during the first 24 hours after chemotherapy administration is considered acute N&V.[10]
• Delayed (or late) N&V: N&V that occurs more than 24 hours after chemotherapy administration is considered delayed, or late, N&V. Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more consecutive days.
• Anticipatory N&V (ANV): ANV is nausea and/or vomiting that occurs before a new cycle of chemotherapy is begun, in response to conditioned stimuli such as the smells, sights, and sounds of the treatment room. ANV is a classically conditioned response that typically occurs after three or four chemotherapy treatments after which the patient experienced acute or delayed N&V.
• Breakthrough N&V: Vomiting that occurs within 5 days of prophylactic use of antiemetics and requires rescue is termed breakthrough N&V.
• Refractory N&V: N&V that does not respond to treatment.
• Chronic N&V in advanced-cancer patients: Chronic N&V in patients with advanced cancer is N&V associated with a variety of potential etiologies. A definitive understanding of cause is neither well known nor well researched, but potential causal factors include gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic chemotherapy–induced, and radiation-induced mechanisms.[11]

References

1. Farrell C, Brearley SG, Pilling M, et al.: The impact of chemotherapy-related nausea on patients' nutritional status, psychological distress and quality of life. Support Care Cancer 21 (1): 59-66, 2013. [PubMed: 22610269]
2. Dranitsaris G, Bouganim N, Milano C, et al.: Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11 (1): 14-21, 2013. [PubMed: 22763232]
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. [PMC free article: PMC3503672] [PubMed: 23300365]
4. Sullivan JR, Leyden MJ, Bell R: Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion. N Engl J Med 309 (13): 796, 1983. [PubMed: 6684209]
5. Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: a review. Ann Oncol 2 (2): 107-14, 1991. [PubMed: 2054311]
6. Roila F, Tonato M, Basurto C, et al.: Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 5 (1): 141-9, 1987. [PubMed: 3543234]
7. Kris MG, Urba SG, Schwartzberg LS: Clinical roundtable monograph. Treatment of chemotherapy-induced nausea and vomiting: a post-MASCC 2010 discussion. Clin Adv Hematol Oncol 9 (1): suppl 1-15, 2011. [PubMed: 21370520]
8. Hesketh PJ: Chemotherapy-induced nausea and vomiting. N Engl J Med 358 (23): 2482-94, 2008. [PubMed: 18525044]
9. Grunberg SM, Osoba D, Hesketh PJ, et al.: Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--an update. Support Care Cancer 13 (2): 80-4, 2005. [PubMed: 15599601]
10. Wickham R: Nausea and vomiting. In: Yarbo CH, Frogge MH, Goodman M, eds.: Cancer Symptom Management. 2nd ed. Sudbury, Mass: Jones and Bartlett Publishers, 1999, pp 228-263.
11. Schwartzberg L: Chemotherapy-induced nausea and vomiting: state of the art in 2006. J Support Oncol 4 (2 Suppl 1): 3-8, 2006. [PubMed: 16499138]
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 December 30, 2015.

Prevalence

The prevalence of anticipatory nausea and vomiting (emesis) (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 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 factors that correlate with the incidence of ANV in hopes of developing a list of risk factors. There is currently no agreement on which factors predict ANV. A patient with fewer than three of the first eight characteristics listed below, however, is unlikely to develop ANV, and screening 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 last chemotherapy session.
3. Posttreatment nausea described as moderate, severe, or intolerable.
4. Posttreatment vomiting described as moderate, severe, or intolerable.
5. Feeling warm or hot all over after last chemotherapy session.
6. Susceptibility to motion sickness.
7. 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 is the recommended treatment. Referral to a psychologist or other mental health professional with specific training and experience in working with cancer patients is recommended when ANV is identified. The earlier ANV is identified, the more likely treatment will be effective; thus, early screening and referral are essential. However, physicians and nurses underestimate the incidence of chemotherapy-induced N&V.[26][Level of evidence: II]

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

References

1. Andrykowski MA: Defining anticipatory nausea and vomiting: differences among cancer chemotherapy patients who report pretreatment nausea. J Behav Med 11 (1): 59-69, 1988. [PubMed: 3367372]
2. Morrow GR, Roscoe JA, Kirshner JJ, et al.: Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 6 (3): 244-7, 1998. [PubMed: 9629877]
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. [PMC free article: PMC1968891] [PubMed: 8180031]
4. Fernández-Marcos A, Martín M, Sanchez JJ, et al.: Acute and anticipatory emesis in breast cancer patients. Support Care Cancer 4 (5): 370-7, 1996. [PubMed: 8883231]
5. Roscoe JA, Morrow GR, Hickok JT, et al.: Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 20 (2): 113-21, 2000. [PubMed: 10989249]
6. Reesal RT, Bajramovic H, Mai F: Anticipatory nausea and vomiting: a form of chemotherapy phobia? Can J Psychiatry 35 (1): 80-2, 1990. [PubMed: 1969324]
7. Stockhorst U, Klosterhalfen S, Steingruber HJ: Conditioned nausea and further side-effects in cancer chemotherapy: a review. Journal of Psychophysiology 12 (suppl 1): 14-33, 1998.
8. Morrow GR, Rosenthal SN: Models, mechanisms and management of anticipatory nausea and emesis. Oncology 53 (Suppl 1): 4-7, 1996. [PubMed: 8692550]
9. Montgomery GH, Bovbjerg DH: The development of anticipatory nausea in patients receiving adjuvant chemotherapy for breast cancer. Physiol Behav 61 (5): 737-41, 1997. [PubMed: 9145945]
10. Bovbjerg DH, Redd WH, Jacobsen PB, et al.: An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med 54 (6): 623-37, 1992 Nov-Dec. [PubMed: 1454956]
11. Morrow GR, Roscoe JA, Hickok JT: Nausea and vomiting. In: Holland JC, Breitbart W, Jacobsen PB, et al., eds.: Psycho-oncology. New York, NY: Oxford University Press, 1998, pp 476-484.
12. Andrykowski MA, Redd WH, Hatfield AK: Development of anticipatory nausea: a prospective analysis. J Consult Clin Psychol 53 (4): 447-54, 1985. [PubMed: 4031199]
13. Roscoe JA, Morrow GR, Hickok JT, et al.: Biobehavioral factors in chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw 2 (5): 501-8, 2004. [PubMed: 19780257]
14. Kvale G, Psychol C, Hugdahl K: Cardiovascular conditioning and anticipatory nausea and vomiting in cancer patients. Behav Med 20 (2): 78-83, 1994 Summer. [PubMed: 7803940]
15. Montgomery GH, Tomoyasu N, Bovbjerg DH, et al.: Patients' pretreatment expectations of chemotherapy-related nausea are an independent predictor of anticipatory nausea. Ann Behav Med 20 (2): 104-9, 1998 Spring. [PubMed: 9989316]
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. [PMC free article: PMC3027302] [PubMed: 18243641]
17. Tomoyasu N, Bovbjerg DH, Jacobsen PB: Conditioned reactions to cancer chemotherapy: percent reinforcement predicts anticipatory nausea. Physiol Behav 59 (2): 273-6, 1996. [PubMed: 8838605]
18. Chin SB, Kucuk O, Peterson R, et al.: Variables contributing to anticipatory nausea and vomiting in cancer chemotherapy. Am J Clin Oncol 15 (3): 262-7, 1992. [PubMed: 1590283]
19. Carey MP, Burish TG: Etiology and treatment of the psychological side effects associated with cancer chemotherapy: a critical review and discussion. Psychol Bull 104 (3): 307-25, 1988. [PubMed: 3062654]
20. Lyles JN, Burish TG, Krozely MG, et al.: Efficacy of relaxation training and guided imagery in reducing the aversiveness of cancer chemotherapy. J Consult Clin Psychol 50 (4): 509-24, 1982. [PubMed: 6749917]
21. Redd WH, Andresen GV, Minagawa RY: Hypnotic control of anticipatory emesis in patients receiving cancer chemotherapy. J Consult Clin Psychol 50 (1): 14-9, 1982. [PubMed: 7056907]
22. Morrow GR, Morrell C: Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 307 (24): 1476-80, 1982. [PubMed: 6128673]
23. Burish TG, Shartner CD, Lyles JN: Effectiveness of multiple muscle-site EMG biofeedback and relaxation training in reducing the aversiveness of cancer chemotherapy. Biofeedback Self Regul 6 (4): 523-35, 1981. [PubMed: 7034793]
24. Kolko DJ, Rickard-Figueroa JL: Effects of video games on the adverse corollaries of chemotherapy in pediatric oncology patients: a single-case analysis. J Consult Clin Psychol 53 (2): 223-8, 1985. [PubMed: 3858296]
25. Vasterling J, Jenkins RA, Tope DM, et al.: Cognitive distraction and relaxation training for the control of side effects due to cancer chemotherapy. J Behav Med 16 (1): 65-80, 1993. [PubMed: 8433358]
26. Chan CW, Cheng KK, Lam LW, et al.: Psycho-educational intervention for chemotherapy-associated nausea and vomiting in paediatric oncology patients: a pilot study. Hong Kong Med J 14 (5 Suppl): 32-5, 2008. [PubMed: 18941272]
27. Rock EM, Limebeer CL, Parker LA: Anticipatory nausea in animal models: a review of potential novel therapeutic treatments. Exp Brain Res 232 (8): 2511-34, 2014. [PubMed: 24792499]

Acute Nausea and Vomiting (N&V)

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

Other risk factors include the following:[10]

• Poor control with previous chemotherapy.
• Female gender.
• Age younger than 50 years.
• Experience with previous chemotherapy.
• History of motion sickness.
• History of 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.[11]

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

  -

  Cisplatin.

  -

  Mechlorethamine.

  -

  Streptozotocin.

  -

  Cyclophosphamide, 1,500 mg/m² or more.

  -

  Carmustine.

  -

  Dacarbazine.

  -

  Dactinomycin.

• Moderate risk: Emesis that has been documented to occur in 30% to 90% of patients:

  -

  Carboplatin.

  -

  Cyclophosphamide, less than 1,500 mg/m².

  -

  Daunorubicin.

  -

  Doxorubicin.

  -

  Epirubicin.

  -

  Idarubicin.

  -

  Oxaliplatin.

  -

  Cytarabine, more than 1 g/m².

  -

  Ifosfamide.

  -

  Irinotecan.

• Low risk: Emesis that has been documented to occur in 10% to 30% of patients:

  -

  Mitoxantrone.

  -

  Paclitaxel.

  -

  Docetaxel.

  -

  Mitomycin.

  -

  Topotecan.

  -

  Gemcitabine.

  -

  Etoposide.

  -

  Pemetrexed.

  -

  Methotrexate.

  -

  Cytarabine, less than 1,000 mg/m².

  -

  Fluorouracil.

  -

  Bortezomib.

  -

  Cetuximab.

  -

  Trastuzumab.

• Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:

  -

  Vinorelbine.

  -

  Bevacizumab.

  -

  Rituximab.

  -

  Bleomycin.

  -

  Vinblastine.

  -

  Vincristine.

  -

  Busulfan.

  -

  Fludarabine.

  -

  Cladribine.

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.[1,12,13]

• 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 (Emesis) (N&V) section of this summary for more information.

References

1. Hesketh PJ, Sanz-Altamira P, Bushey J, et al.: Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. Support Care Cancer 20 (5): 1043-7, 2012. [PubMed: 21553313]
2. Schwartzberg L: Addressing the value of novel therapies in chemotherapy-induced nausea and vomiting. Expert Rev Pharmacoecon Outcomes Res 14 (6): 825-34, 2014. [PubMed: 25227565]
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. [PMC free article: PMC7657206] [PubMed: 23480814]
4. Roscoe JA, Morrow GR, Hickok JT, et al.: Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 20 (2): 113-21, 2000. [PubMed: 10989249]
5. Viale PH, Grande C, Moore S: Efficacy and cost: avoiding undertreatment of chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs 16 (4): E133-41, 2012. [PubMed: 22842698]
6. Dranitsaris G, Bouganim N, Milano C, et al.: Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 11 (1): 14-21, 2013. [PubMed: 22763232]
7. Kris MG, Urba SG, Schwartzberg LS: Clinical roundtable monograph. Treatment of chemotherapy-induced nausea and vomiting: a post-MASCC 2010 discussion. Clin Adv Hematol Oncol 9 (1): suppl 1-15, 2011. [PubMed: 21370520]
8. Phillips RS, Gopaul S, Gibson F, et al.: Antiemetic medication for prevention and treatment of chemotherapy induced nausea and vomiting in childhood. Cochrane Database Syst Rev (9): CD007786, 2010. [PubMed: 20824866]
9. Olver I, Clark-Snow RA, Ballatori E, et al.: Guidelines for the control of nausea and vomiting with chemotherapy of low or minimal emetic potential. Support Care Cancer 19 (Suppl 1): S33-6, 2011. [PubMed: 20803222]
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. [PubMed: 16717289]
11. Navari RM: Antiemetic control: toward a new standard of care for emetogenic chemotherapy. Expert Opin Pharmacother 10 (4): 629-44, 2009. [PubMed: 19284365]
12. Geling O, Eichler HG: Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 23 (6): 1289-94, 2005. [PubMed: 15718327]
13. 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. [PMC free article: PMC3396799] [PubMed: 22942805]

Phenothiazines

Phenothiazines act on dopaminergic receptors at the CTZ, possibly at other central nervous system (CNS) centers, and peripherally. With the exception of thioridazine, many phenothiazines possess antiemetic activity, including chlorpromazine given in the 10- to 50-mg dose range orally, IM, IV, and rectally (pediatric dose for patients >12 years: 10 mg every 6–8 hours; for patients <12 years: 5 mg every 6–8 hours); and perphenazine.

The primary consideration in selecting phenothiazines are differences in their adverse effect profiles, which substantially correlate with their structural classes. Generally, aliphatic phenothiazines (e.g., chlorpromazine, methotrimeprazine) produce sedation and anticholinergic effects, while piperazines (e.g., prochlorperazine, perphenazine, fluphenazine) are associated with less sedation but greater incidence of extrapyramidal reactions (EPRs) (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 extrapyramidal side effects. Phenothiazines may be of particular value in treating patients who experience delayed N&V (postacute phase symptoms) on cisplatin regimens.[15-19][Level of evidence: I]

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 administered IM or IV, typically from 1 to 2.5 mg every 2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[20,21] Haloperidol is administered IM, IV, or orally, typically from 1 to 4 mg every 2 to 6 hours.[22] Results of a small, uncontrolled, open-label study showed some efficacy for haloperidol in palliative care patients.[23] Both agents may produce EPRs, akathisia, hypotension, and sedation.

Substituted Benzamides

Metoclopramide is a substituted benzamide, which, before serotonin (5-HT₃) receptor antagonists were introduced, was considered the most effective single antiemetic agent against highly emetogenic chemotherapy such as cisplatin. Although metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it is most effective against acute vomiting when given IV at high doses (e.g., 0.5–3 mg/kg/dose), probably because it is a weak competitive antagonist (relative to other serotonin antagonists) at 5-HT₃ receptors. It may act on the CTZ and the periphery. Metoclopramide also increases lower esophageal sphincter pressure and enhances the rate of gastric emptying, which may factor into its overall antiemetic effect. It can be administered IV at the U.S. Food and Drug Administration (FDA)–approved dose of 1 to 2 mg/kg every 2 hours (or less frequently) for three to five doses. Metoclopramide has also been safely given by IV bolus injection at higher single doses (up to 6 mg/kg) and by continuous IV infusion, with or without a loading bolus dose, with efficacy comparable to that of multiple intermittent dosing schedules.[24-26]

Metoclopramide is associated with akathisia and dystonic extrapyramidal effects; akathisia is seen more frequently in patients older than 30 years, and dystonic extrapyramidal effects are seen more commonly in patients younger than 30 years. Diphenhydramine, benztropine mesylate, and trihexyphenidyl are commonly used prophylactically or therapeutically to pharmacologically antagonize EPRs.[27] While cogwheeling rigidity, acute dystonia, and tremor are responsive to anticholinergic medications, akathisia—the subjective sense of restlessness or inability to sit still—is best treated by the following:

• Switching to a lower potency neuroleptic for vomiting, if possible.
• Lowering the dose.
• Adding a benzodiazepine (e.g., lorazepam).

Although less commonly used in the United States, metoclopramide is still very commonly used in other countries.

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 FDA, is available internationally. 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.[28-30] 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, constipation, and/or diarrhea. Multiple studies have shown that the 5-HT₃ receptor antagonists are most effective when given in conjunction with steroids.

Substance P Antagonists (NK-1 Receptor 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, and netupitant, have been developed.

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.[84,85][Level of evidence: I][86]

Steroids are often given IV before chemotherapy and may or may not be repeated. Dosages and administration schedules are selected empirically. Dexamethasone is often the treatment of choice for N&V in patients receiving radiation to the brain, as it also reduces cerebral edema. It is administered orally or IV in the dose range of 8 mg to 40 mg (pediatric dose: 0.25–0.5 mg/kg).[87,88] 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.[85,89]

Dexamethasone is also used orally for delayed N&V. Long-term corticosteroid use, however, is inappropriate and may cause substantial morbidity, including the following:[90-92]

• 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).[93] As previously shown with metoclopramide, numerous studies have demonstrated that dexamethasone potentiates the antiemetic properties of 5-HT₃–blocking agents.[90,94] If administered IV, 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.[95-98]

Benzodiazepines

Benzodiazepines such as lorazepam, midazolam, 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.[90-92] Benzodiazepines have not demonstrated intrinsic antiemetic activity as single agents; therefore, their place in antiemetic prophylaxis and treatment is adjunctive to other antiemetic agents.[99] 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 EPRs, especially akathisia, associated with dopaminergic receptor antagonist antiemetics.

Other Pharmacologic Agents

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.

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112. 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. [PubMed: 12067777]
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Correlates

Patients receiving radiation to the gastrointestinal (GI) tract or brain have the greatest potential for nausea and vomiting (N&V) as side effects. Because cells of the GI tract are dividing quickly, they are quite sensitive to radiation therapy. Radiation to the brain is believed to stimulate the brain’s vomiting center or chemoreceptor trigger zone. Similar to chemotherapy, radiation dose factors also play a role in determining the possible occurrence of N&V. In general, the higher the daily fractional dose and the greater the amount of tissue that is irradiated, the higher the potential for N&V. In addition, the larger the amount of GI tract irradiated (particularly for fields that include the small intestine and stomach), the higher the potential for N&V. Total-body irradiation before bone marrow transplant, for example, has a high probability of inducing N&V as acute side effects.

Prevalence

N&V from radiation may be acute and self-limiting, usually occurring 30 minutes to several hours after treatment. Patients report that symptoms improve on days that they are not being treated. There are also cumulative effects that may occur in patients receiving radiation therapy to the GI tract.[1]

Treatment

Complete control rates with 5-HT₃ receptor antagonists for total-body irradiation vary from 50% to 90%.[2-4] The role of corticosteroids in combination with 5-HT₃ receptor antagonists has not been studied.

References

1. Kris MG, Hesketh PJ, Somerfield MR, et al.: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24 (18): 2932-47, 2006. [PubMed: 16717289]
2. Spitzer TR, Grunberg SM, Dicato MA: Antiemetic strategies for high-dose chemoradiotherapy-induced nausea and vomiting. Support Care Cancer 6 (3): 233-6, 1998. [PubMed: 9629875]
3. Prentice HG, Cunningham S, Gandhi L, et al.: Granisetron in the prevention of irradiation-induced emesis. Bone Marrow Transplant 15 (3): 445-8, 1995. [PubMed: 7599570]
4. Schwella N, König V, Schwerdtfeger R, et al.: Ondansetron for efficient emesis control during total body irradiation. Bone Marrow Transplant 13 (2): 169-71, 1994. [PubMed: 8205086]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of nausea and vomiting (emesis) (N&V). 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 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)
• Eric Sandler, MD (Nemours Children's Clinic)

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

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Nausea and Vomiting. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/treatment/side-effects/nausea/nausea-hp-pdq. Accessed <MM/DD/YYYY>.

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