Table of Contents Purpose of This PDQ Summary Overview
Neurophysiology General Risk Factors and Etiologies Anticipatory Nausea and Vomiting Acute/Delayed Emesis Etiology Prevention of Acute/Delayed Emesis Nausea, Vomiting, Constipation, and Bowel Obstruction in Advanced Cancer Nonpharmacologic Management of Nausea and Vomiting Radiation Therapy Get More Information From NCI Changes to This Summary (04/22/2009) Questions or Comments About This Summary More Information
Purpose of This PDQ Summary
This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of nausea and vomiting. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board 1.
Information about the following is included in this summary:
- Anticipatory nausea and vomiting.
- Acute/delayed nausea and vomiting.
- Chronic nausea and vomiting in patients with advanced cancer.
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for cancer patients during and after cancer treatment. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version 2, which is written in less technical language, and in Spanish 3. Overview
Prevention and control of nausea and vomiting are paramount in the treatment of
cancer patients. Nausea and vomiting can result in serious metabolic
derangements, nutritional depletion and anorexia, deterioration of patients’
physical and mental status, esophageal tears, fractures, wound dehiscence,
withdrawal from potentially useful and curative antineoplastic treatment, and
degeneration of self-care and functional ability. Despite advances in
pharmacologic and nonpharmacologic management, nausea and vomiting remain two of
the more distressing and feared side effects to cancer patients and their
families, and incidence may be underestimated by physicians and nurses.[1-5]
Introduction
Nausea is a subjective phenomenon of an unpleasant, wavelike sensation
experienced in the back of the throat and/or the epigastrium that may or may
not culminate in vomiting. Vomiting is the forceful expulsion of the contents
of the stomach, duodenum, or jejunum through the oral cavity. Retching is
gastric and esophageal movements of vomiting without expulsion of vomitus and
is also referred to as dry heaves.
Classifications
Various classifications of nausea and vomiting (N&V) have been used,[1,6]
including acute, delayed, late or persistent, chronic, anticipatory,
breakthrough, or refractory, as well as distinctions related to type of
treatment (e.g., chemotherapy- or radiation-induced), and clinical course (e.g.,
advanced or terminal disease).[7,8] Despite this variety, the most commonly
described types are acute, delayed, and anticipatory chemotherapy-induced N&V;
and chronic N&V in advanced cancer patients. Although there are no standard
definitions, the following are commonly used to classify the different types.
-
Acute nausea and vomiting (or emesis): N&V experienced during the first 24-hour
period after chemotherapy administration is considered acute N&V.[1]
-
Delayed (or late) nausea and vomiting (or emesis): N&V that occurs more than 24
hours after chemotherapy administration is considered delayed, or late, N&V.
Delayed N&V is associated with cisplatin, cyclophosphamide, and other drugs
(e.g., doxorubicin and ifosfamide) given at high doses or on 2 or more
consecutive days.
-
Anticipatory nausea and vomiting (ANV): ANV is nausea and/or vomiting that
occur prior to the beginning of a new cycle of chemotherapy, in response to
conditioned stimuli such as the smells, sights, and sounds of the treatment
room. ANV is a classically conditioned response that typically occurs after three
or four prior chemotherapy treatments, following which the person experienced
acute or delayed N&V.
-
Chronic nausea and vomiting (or emesis) in advanced cancer patients: Chronic
nausea and vomiting in the advanced cancer patient is N&V associated with a
variety of potential etiologies. A definitive understanding of cause is not
well known, nor well researched, but potential causal factors include
gastrointestinal, cranial, metabolic, drug-induced (e.g., morphine), cytotoxic
chemotherapy, and radiation-induced mechanisms.[9]
Table 1. Criteria for Grading Severity of Nausea and Vomiting*
|
Grade 1
|
Grade 2
|
Grade 3
|
Grade 4
|
Grade 5
|
*Adapted from Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS.
|
Nausea |
Loss of appetite without alteration in eating habits |
Oral intake decreased without significant weight loss, dehydration or malnutrition; IV fluids indicated <24 h |
Inadequate oral caloric or fluid intake; IV fluids, tube feedings, or TPN indicated ≥24 h |
Life-threatening consequences |
Death |
Vomiting |
1 episode in 24 h |
2–5 episodes in 24 h; IV fluids indicated <24 h |
≥6 episodes in 24 h; IV fluids, or TPN indicated ≥24 h |
Life-threatening consequences |
Death |
References
-
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.
-
Coates A, Abraham S, Kaye SB, et al.: On the receiving end--patient perception of the side-effects of cancer chemotherapy. Eur J Cancer Clin Oncol 19 (2): 203-8, 1983.
[PUBMED Abstract]
-
Craig JB, Powell BL: The management of nausea and vomiting in clinical oncology. Am J Med Sci 293 (1): 34-44, 1987.
[PUBMED Abstract]
-
Passik SD, Kirsh KL, Rosenfeld B, et al.: The changeable nature of patients' fears regarding chemotherapy: implications for palliative care. J Pain Symptom Manage 21 (2): 113-20, 2001.
[PUBMED Abstract]
-
Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.
[PUBMED Abstract]
-
Pisters KM, Kris MG: Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 165-199.
-
Fallon BG: Nausea and vomiting unrelated to cancer treatment. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 179-189.
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Allan SG: Nausea and vomiting. In: Doyle D, Hanks GW, MacDonald N, eds.: Oxford Textbook of Palliative Medicine. 2nd ed. New York, NY: Oxford University Press, 1998, pp 282-290.
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Schwartzberg L: Chemotherapy-induced nausea and vomiting: state of the art in 2006. J Support Oncol 4 (2 Suppl 1): 3-8, 2006.
[PUBMED Abstract]
Neurophysiology
Progress has been made in understanding the neurophysiologic mechanisms that
control nausea and vomiting. Both are controlled or mediated by the central
nervous system but by different mechanisms. Nausea is mediated through the
autonomic nervous system. Vomiting results from the stimulation of a complex
reflex that is coordinated by a putative true vomiting center, which may be
located in the dorsolateral reticular formation near the medullary respiratory
centers. The vomiting center presumably receives convergent afferent
stimulation from several central neurologic pathways, including the
following:[1,2]
- A chemoreceptor trigger zone (CTZ).
- The cerebral cortex and the limbic system in response to sensory
stimulation (particularly smell and taste), psychologic distress, and pain.
- The vestibular-labyrinthine apparatus of the inner ear, in response to body
motion.
- Peripheral stimuli from visceral organs and vasculature (via vagal and
spinal sympathetic nerves) as a result of exogenous chemicals and
endogenous substances that accumulate during inflammation, ischemia, and
irritation.
The CTZ is located in the area postrema, one of the circumventricular regions
of the brain on the dorsal surface of the medulla oblongata at the caudal end
of the fourth ventricle. Unlike vasculature within the blood-brain diffusion
barrier, the area postrema is highly vascularized with fenestrated blood
vessels, which lack tight junctions (zonae occludentes) between capillary
endothelial cells. The CTZ is anatomically specialized to readily sample
elements present in the circulating blood and cerebrospinal fluid (CSF).[3,4]
Currently, evidence indicates that acute emesis following chemotherapy is
initiated by the release of neurotransmitters from cells that are susceptible
to the presence of toxic substances in the blood or CSF. Area postrema cells
in the CTZ and enterochromaffin cells within the intestinal mucosa are
implicated in initiating and propagating afferent stimuli that ultimately
converge on central structures corresponding to a vomiting center. The
relative contribution from these multiple pathways culminating in nausea and
vomiting symptoms is complex and is postulated to account for the variable
emetogenicity (intrinsic emetogenicity and mitigating factors, i.e., dosage,
administration route, exposure duration) and emetogenic profile (i.e., time to
onset, symptom severity, and duration) of agents.
References
-
Pisters KM, Kris MG: Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds.: Principles and Practice of Supportive Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 1998, pp 165-199.
-
Berger AM, Clark-Snow RA: Nausea and vomiting. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997, 2705-2712.
-
Andrews PL, Hawthorn J: The neurophysiology of vomiting. Baillieres Clin Gastroenterol 2 (1): 141-68, 1988.
[PUBMED Abstract]
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Miller AD, Leslie RA: The area postrema and vomiting. Front Neuroendocrinol 15 (4): 301-20, 1994.
[PUBMED Abstract]
General Risk Factors and Etiologies
Not all cancer patients will experience nausea and/or vomiting. The most
common causes are emetogenic chemotherapy drugs and radiation therapy to the
gastrointestinal (GI) tract, liver, or brain. Several patient characteristics have
also been identified. These include incidence and severity of nausea and
vomiting (N&V) during past courses of chemotherapy, history of chronic alcohol
use, age, and gender. Patients with poor control of N&V during prior
chemotherapy cycles are likely to experience N&V in subsequent cycles. N&V is
less likely in patients with a history of chronic, high alcohol intake,[1]
and more likely in women [2,3] and younger patients (<50 years).[2]
Other possible causes include fluid and electrolyte imbalances such as
hypercalcemia, volume depletion, or water intoxication; tumor invasion or
growth in the GI tract, liver, or central nervous system,
especially the posterior fossa; constipation; certain drugs such as opioids;
infection or septicemia; or uremia. The psychological variables of state
anxiety (level of anxiety during chemotherapy infusions), and pretreatment
expectations for nausea and vomiting (self-fulfilling prophecy) have also been
investigated as predictors of posttreatment nausea.[4-9] At present, studies
have found mixed results that vary due to different research methods. Better
designed studies, however, have found state anxiety and patient
expectations for nausea to be predictors of posttreatment nausea, even after
controlling for known physiological predictors (susceptibility to nausea during
pregnancy and motion sickness) and emetogenic potential of the chemotherapy
drugs.[6-8,10,11] It is important to note, however, that patients’ fears and
expectations about chemotherapy can be variable and change over time.[12] In a
longitudinal study [12] patients’ anticipatory fears of vomiting decreased
significantly from pretreatment to a period 3 to 6 months later, particularly
when their chemotherapy included antiemetic medications.
Clinicians treating N&V must be alert to all potential causes and factors,
especially in cancer patients who may be receiving combinations of several
treatments and medications. (Refer to the PDQ summary on Pain 5 for more
information on opioid-induced nausea and vomiting.)
References
-
Sullivan JR, Leyden MJ, Bell R: Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion. N Engl J Med 309 (13): 796, 1983.
[PUBMED Abstract]
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Tonato M, Roila F, Del Favero A: Methodology of antiemetic trials: a review. Ann Oncol 2 (2): 107-14, 1991.
[PUBMED Abstract]
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Roila F, Tonato M, Basurto C, et al.: Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: a randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 5 (1): 141-9, 1987.
[PUBMED Abstract]
-
Cassileth BR, Lusk EJ, Bodenheimer BJ, et al.: Chemotherapeutic toxicity--the relationship between patients' pretreatment expectations and posttreatment results. Am J Clin Oncol 8 (5): 419-25, 1985.
[PUBMED Abstract]
-
Andrykowski MA, Gregg ME: The role of psychological variables in post-chemotherapy nausea: anxiety and expectation. Psychosom Med 54 (1): 48-58, 1992 Jan-Feb.
[PUBMED Abstract]
-
Jacobsen PB, Andrykowski MA, Redd WH, et al.: Nonpharmacologic factors in the development of posttreatment nausea with adjuvant chemotherapy for breast cancer. Cancer 61 (2): 379-85, 1988.
[PUBMED Abstract]
-
Haut MW, Beckwith BE, Laurie JA, et al.: Postchemotherapy nausea and vomiting in cancer patients receiving outpatient chemotherapy. Journal of Psychosocial Oncology 9(1): 117-130, 1991.
-
Roscoe JA, Hickok JT, Morrow GR: Patient expectations as predictor of chemotherapy-induced nausea. Ann Behav Med 22 (2): 121-6, 2000 Spring.
[PUBMED Abstract]
-
Hickok JT, Roscoe JA, Morrow GR: The role of patients' expectations in the development of anticipatory nausea related to chemotherapy for cancer. J Pain Symptom Manage 22 (4): 843-50, 2001.
[PUBMED Abstract]
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Roscoe JA, Bushunow P, Morrow GR, et al.: Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer 101 (11): 2701-8, 2004.
[PUBMED Abstract]
-
Higgins SC, Montgomery GH, Bovbjerg DH: Distress before chemotherapy predicts delayed but not acute nausea. Support Care Cancer 15 (2): 171-7, 2007.
[PUBMED Abstract]
-
Passik SD, Kirsh KL, Rosenfeld B, et al.: The changeable nature of patients' fears regarding chemotherapy: implications for palliative care. J Pain Symptom Manage 21 (2): 113-20, 2001.
[PUBMED Abstract]
Anticipatory Nausea and Vomiting
Prevalence
The prevalence of anticipatory nausea and vomiting (ANV) has varied, owing to
changing definitions and assessment methods.[1] However, anticipatory nausea
(AN) appears to occur in approximately 29% of patients receiving chemotherapy,
or about 1:3, while anticipatory vomiting (AV) appears to occur in 11% of
patients, or about 1:10.[2] With the introduction of new pharmacologic agents
(5-HT3 receptor antagonists), it was anticipated that the prevalence of ANV
might decline; however, studies have shown mixed results. One study found a
lower incidence of ANV,[3] and three studies found comparable incidence
rates.[2,4,5] It appears that the 5-HT3 agents reduce postchemotherapy
vomiting, but not postchemotherapy nausea,[2,5] and the resulting impact on ANV
is unclear.
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 prior pairings or learning trials. In
cancer chemotherapy the first few chemotherapy infusions are the learning
trials. The chemotherapy drugs are the unconditioned stimuli that elicit
postchemotherapy nausea and vomiting (in some patients). They are paired with
a variety of other neutral, environmental stimuli (e.g., smells of the setting,
oncology nurse, chemotherapy room). These previously neutral stimuli then
become conditioned stimuli and elicit ANV in future chemotherapy cycles. ANV
is not an indication of psychopathology, but rather a learned response that, in
other life situations (e.g., food poisoning) results in adaptive avoidance. A
variety of correlational studies provide empirical support for classical
conditioning. For example, the prevalence of ANV prior to any chemotherapy is
very rare, and few patients ever experience ANV without prior postchemotherapy
nausea.[8] Also, most studies have found a higher probability of ANV with
increasing numbers of chemotherapy infusions, and the intensity of ANV
increases as patients get closer to the actual time of their infusion.[9] In
one experimental study, it was shown that a novel beverage could become a
conditioned stimulus to nausea when paired with several chemotherapy
treatments.[10]
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 following the first chemotherapy infusion could identify those
patients at increased risk.[11]
Variables Found to Correlate With ANV
- Age younger than 50 years.
- Nausea/vomiting after last chemotherapy session.
-
Posttreatment nausea described as moderate, severe, or intolerable.
- Posttreatment vomiting described as moderate, severe, or intolerable.
- Feeling warm or hot all over after last chemotherapy session.
-
Susceptibility to motion sickness.
- Sweating after last chemotherapy session.
- Generalized weakness after last chemotherapy session.
- Female gender.
- High-state anxiety (anxiety reactive to specific situations).[12,13]
- Greater reactivity of the autonomic nervous system and slower reaction
time.[14]
- Patient expectations of chemotherapy-related nausea before beginning
treatment.[15,16]
- Percentage of infusions of chemotherapy followed by nausea.[17]
- Postchemotherapy dizziness.
- Lightheadedness.
- Longer latency of onset of
posttreatment nausea and vomiting.[18]
- Emetogenic potential of various chemotherapeutic agents. Patients receiving drugs with a moderate-to-severe potential for
posttreatment nausea and vomiting are more likely to develop ANV.[12]
- 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 progressive muscle relaxation with guided imagery,[20] hypnosis,[21]
systematic desensitization,[22] electromyography (EMG) and thermal biofeedback,[23] and
distraction via the use of video games.[24,25] Progressive muscle relaxation
with guided imagery, hypnosis, and systematic desensitization has been studied
the most and is the recommended treatment. Referral to a psychologist or
other mental health professional with specific training and experience in
working with cancer patients is recommended when ANV is identified. The
earlier it is identified, the more likely treatment will be effective, and
thus early screening and referral are essential.
In addition, physicians and nurses underestimate the incidence of chemotherapy-induced nausea and vomiting.[26]
References
-
Andrykowski MA: Defining anticipatory nausea and vomiting: differences among cancer chemotherapy patients who report pretreatment nausea. J Behav Med 11 (1): 59-69, 1988.
[PUBMED Abstract]
-
Morrow GR, Roscoe JA, Kirshner JJ, et al.: Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 6 (3): 244-7, 1998.
[PUBMED Abstract]
-
Aapro MS, Kirchner V, Terrey JP: The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: the effect of granisetron. Br J Cancer 69 (5): 957-60, 1994.
[PUBMED Abstract]
-
Fernández-Marcos A, Martín M, Sanchez JJ, et al.: Acute and anticipatory emesis in breast cancer patients. Support Care Cancer 4 (5): 370-7, 1996.
[PUBMED Abstract]
-
Roscoe JA, Morrow GR, Hickok JT, et al.: Nausea and vomiting remain a significant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinical practices. J Pain Symptom Manage 20 (2): 113-21, 2000.
[PUBMED Abstract]
-
Reesal RT, Bajramovic H, Mai F: Anticipatory nausea and vomiting: a form of chemotherapy phobia? Can J Psychiatry 35 (1): 80-2, 1990.
[PUBMED Abstract]
-
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.
-
Morrow GR, Rosenthal SN: Models, mechanisms and management of anticipatory nausea and emesis. Oncology 53 (Suppl 1): 4-7, 1996.
[PUBMED Abstract]
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Montgomery GH, Bovbjerg DH: The development of anticipatory nausea in patients receiving adjuvant chemotherapy for breast cancer. Physiol Behav 61 (5): 737-41, 1997.
[PUBMED Abstract]
-
Bovbjerg DH, Redd WH, Jacobsen PB, et al.: An experimental analysis of classically conditioned nausea during cancer chemotherapy. Psychosom Med 54 (6): 623-37, 1992 Nov-Dec.
[PUBMED Abstract]
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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.
-
Andrykowski MA, Redd WH, Hatfield AK: Development of anticipatory nausea: a prospective analysis. J Consult Clin Psychol 53 (4): 447-54, 1985.
[PUBMED Abstract]
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Roscoe JA, Morrow GR, Hickok JT, et al.: Biobehavioral factors in chemotherapy-induced nausea and vomiting. Journal of the National Comprehensive Cancer Network 2 (5): 501-8, 2004.
-
Kvale G, Psychol C, Hugdahl K: Cardiovascular conditioning and anticipatory nausea and vomiting in cancer patients. Behav Med 20 (2): 78-83, 1994 Summer.
[PUBMED Abstract]
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Montgomery GH, Tomoyasu N, Bovbjerg DH, et al.: Patients' pretreatment expectations of chemotherapy-related nausea are an independent predictor of anticipatory nausea. Ann Behav Med 20 (2): 104-9, 1998 Spring.
[PUBMED Abstract]
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Shelke AR, Roscoe JA, Morrow GR, et al.: Effect of a nausea expectancy manipulation on chemotherapy-induced nausea: a university of Rochester cancer center community clinical oncology program study. J Pain Symptom Manage 35 (4): 381-7, 2008.
[PUBMED Abstract]
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Tomoyasu N, Bovbjerg DH, Jacobsen PB: Conditioned reactions to cancer chemotherapy: percent reinforcement predicts anticipatory nausea. Physiol Behav 59 (2): 273-6, 1996.
[PUBMED Abstract]
-
Chin SB, Kucuk O, Peterson R, et al.: Variables contributing to anticipatory nausea and vomiting in cancer chemotherapy. Am J Clin Oncol 15 (3): 262-7, 1992.
[PUBMED Abstract]
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Carey MP, Burish TG: Etiology and treatment of the psychological side effects associated with cancer chemotherapy: a critical review and discussion. Psychol Bull 104 (3): 307-25, 1988.
[PUBMED Abstract]
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Lyles JN, Burish TG, Krozely MG, et al.: Efficacy of relaxation training and guided imagery in reducing the aversiveness of cancer chemotherapy. J Consult Clin Psychol 50 (4): 509-24, 1982.
[PUBMED Abstract]
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Redd WH, Andresen GV, Minagawa RY: Hypnotic control of anticipatory emesis in patients receiving cancer chemotherapy. J Consult Clin Psychol 50 (1): 14-9, 1982.
[PUBMED Abstract]
-
Morrow GR, Morrell C: Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. N Engl J Med 307 (24): 1476-80, 1982.
[PUBMED Abstract]
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Burish TG, Shartner CD, Lyles JN: Effectiveness of multiple muscle-site EMG biofeedback and relaxation training in reducing the aversiveness of cancer chemotherapy. Biofeedback Self Regul 6 (4): 523-35, 1981.
[PUBMED Abstract]
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Kolko DJ, Rickard-Figueroa JL: Effects of video games on the adverse corollaries of chemotherapy in pediatric oncology patients: a single-case analysis. J Consult Clin Psychol 53 (2): 223-8, 1985.
[PUBMED Abstract]
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Vasterling J, Jenkins RA, Tope DM, et al.: Cognitive distraction and relaxation training for the control of side effects due to cancer chemotherapy. J Behav Med 16 (1): 65-80, 1993.
[PUBMED Abstract]
-
Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.
[PUBMED Abstract]
Acute/Delayed Emesis Etiology
Acute Emesis
- Incidence
- The incidence of acute and delayed nausea and emesis was investigated in highly and moderately emetogenic chemotherapy treatment regimens. Patients were recruited from 14 oncology practices in 6 countries. Overall, more than 35% of patients experienced acute nausea and 13% experienced acute emesis. In patients receiving highly emetogenic chemotherapy, 60% experienced delayed nausea and 50% experienced delayed emesis. In those receiving moderately emetogenic chemotherapy, 52% experienced delayed nausea and 28% experienced delayed emesis.[1] Chemotherapy-induced nausea and vomiting (CINV) was a substantial problem for patients receiving moderately emetogenic chemotherapy in ten community oncology clinics.[2] Thirty-six percent of patients developed acute CINV, and 59% developed delayed CINV.
- Etiologies:
- Chemotherapy is the most common treatment-related cause of nausea and vomiting.
The incidence and severity of acute emesis in persons receiving chemotherapy
varies according to many factors, including the particular drug, dose, schedule
of administration, route, and individual patient variables. In the vast
majority of cancer patients, these symptoms can be prevented or controlled.
- Risk factors for acute emesis include:[3]
- Poor control with prior chemotherapy.
- Female gender.
- Younger age.
- Emetic classifications. The American Society of Clinical Oncology (ASCO) has developed a rating system
for chemotherapeutic agents and their respective risk of acute and delayed
emesis.[3]
- High risk: Emesis that has been documented to occur in more than 90% of patients:
- cisplatin (Platinol)
- mechlorethamine (Mustargen)
- streptozotocin (Zanosar)
- cyclophosphamide (Cytoxan), 1,500 mg/m2 or more
- carmustine (BiCNU)
- dacarbazine (DTIC-Dome)
- dactinomycin
- Moderate risk: Emesis that has been documented to occur in 30% to 90% of
patients:
- carboplatin (Paraplatin)
- cyclophosphamide (Cytoxan), less than 1,500 mg/m2
- daunorubicin (DaunoXome)
- doxorubicin (Adriamycin)
- epirubicin (Pharmorubicin)
- idarubicin (Idamycin)
- oxaliplatin (Eloxatin)
- cytarabine (Cytosar), more than 1 g/m2
- ifosfamide (Ifex)
- irinotecan (Camptosar)
- Low risk: Emesis that has been documented to occur in 10% to 30% of patients:
- mitoxantrone (Novantrone)
- paclitaxel (Taxol)
- docetaxel (Taxotere)
- mitomycin (Mutamycin)
- topotecan (Hycamtin)
- gemcitabine (Gemzar)
- etoposide (Vepesid)
- pemetrexed (Alimta)
- methotrexate (Rheumatrex)
- cytarabine (Cytosar), less than 1,000 mg/m2
- fluorouracil (Efudex)
- bortezomib (Velcade)
- cetuximab (Erbitux)
- trastuzumab (Herceptin)
- Minimal risk: Emesis that has been documented to occur in fewer than 10% of patients:
- vinorelbine (Navelbine)
- bevacizumab (Avastin)
- rituximab (Rituxan)
- bleomycin (Blenoxane)
- vinblastine (Velban)
- vincristine (Oncovin)
- busulphan (Myleran)
- fludarabine (Fludara)
-
2-chlorodeoxyadenosine (Leustatin)
In addition to emetogenic potential, the dose and schedule used are also
extremely important factors. For example, a drug with a low emetogenic
potential given in high doses may cause a dramatic increase in the potential to
induce nausea and vomiting. Standard doses of cytarabine rarely produce nausea
and vomiting, but these are often seen with high doses of this drug. Another
factor to consider is the use of drug combinations. Because most patients
receive combination chemotherapy, the emetogenic potential of all of the drugs
combined and individual drug doses needs to be considered.
Delayed Emesis
Delayed (or late) nausea and vomiting (emesis): Nausea and vomiting that occurs
more than 24 hours after chemotherapy administration is considered delayed or
late nausea and vomiting. Delayed nausea and vomiting is associated with
cisplatin, cyclophosphamide, and other drugs (e.g., doxorubicin and ifosfamide)
given at high doses or on 2 or more consecutive days.
- Etiologies:
- Patients who experience acute emesis with chemotherapy are significantly more
likely to have delayed emesis.
- Risk factors:
- All predicative characteristics for acute emesis should be considered risk
factors for delayed emesis.
- Emetic classifications:
References
-
Grunberg SM, Deuson RR, Mavros P, et al.: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 100 (10): 2261-8, 2004.
[PUBMED Abstract]
-
Cohen L, de Moor CA, Eisenberg P, et al.: Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer 15 (5): 497-503, 2007.
[PUBMED Abstract]
-
Kris MG, Hesketh PJ, Somerfield MR, et al.: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24 (18): 2932-47, 2006.
[PUBMED Abstract]
Prevention of Acute/Delayed Emesis
Antiemetic agents are the most common intervention in the management of
treatment-related nausea and vomiting. The basis for antiemetic therapy is the
neurochemical control of vomiting. Although the exact mechanism is not well
understood, peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ)
are known to contain receptors for serotonin, histamine (H1 and H2), dopamine,
acetylcholine, opioids, and numerous other endogenous neurotransmitters.[1,2]
Many antiemetics act by competitively blocking receptors for these substances,
thereby inhibiting stimulation of peripheral nerves at the CTZ, and perhaps at
the vomiting center. Most drugs with proven antiemetic activity can be
categorized into one of the following groups:
- Competitive antagonists at
dopaminergic (D2 subtype) receptors:
- Phenothiazines.
- Substituted benzamides.
- Butyrophenones.
- Competitive antagonists at serotonergic (5-hydroxytryptamine-3 or
5-HT3 subtype) receptors.
- Substance P antagonists (NK-1 receptor antagonists).
- Corticosteroids.
- Cannabinoids.
- Benzodiazepines.
- Olanzapine.
Although all routes of administration are listed for each
of the following drugs, the intramuscular (IM) route should be used only when no
other access is available. Intramuscular delivery is painful, is associated
with erratic absorption of drug, and may lead to sterile abscess formation or
fibrosis of the tissues. This is particularly important when more than 1 or 2
doses of a drug are to be given.
Phenothiazines
Phenothiazines act on dopaminergic receptors at the CTZ, and perhaps at other central nervous system (CNS) centers, and peripherally. With the exception of thioridazine, many
phenothiazines possess antiemetic activity, including chlorpromazine given in
the 10- to 50-mg dose range orally, IM, intravenously (IV), and
rectally (pediatric dose for older than 12 years: 10 mg every 6–8 hours;
for younger than 12 years: 5 mg every 6–8 hours); thiethylperazine given in
the 5- to 10-mg dose range orally, IM, and IV; and
perphenazine. The primary consideration in selecting among phenothiazines are
differences in their adverse effect profiles, which substantially correlate
with their structural classes. Generally, aliphatic phenothiazines (e.g.,
chlorpromazine, methotrimeprazine) produce sedation and anticholinergic
effects, while piperazines (e.g., prochlorperazine, thiethylperazine,
perphenazine, and fluphenazine) are associated with less sedation but greater
incidence of extrapyramidal reactions (EPRs).
Prochlorperazine
This drug is perhaps the most frequently (and empirically) used antiemetic and,
in low doses, is generally effective in preventing nausea associated with
radiation therapy and in treating nausea and vomiting attributed to very low to
moderately emetogenic chemotherapeutic drugs. It is a phenothiazine and can be
given orally, IM, IV, and rectally. It is usually
given in the 10- to 50-mg dose range (pediatric dose for children who weigh more than 10 kg or who are older than 2 years: orally or rectally, 0.4 mg/kg/d tid–qid; or IM, 0.1–0.15 mg/kg/dose tid–qid, maximum 40 mg/d).
Higher prochlorperazine doses (e.g., 0.2–0.6 mg/kg/dose) are also used
IV for chemotherapy with high emetogenic potential.[3,4]
Phenothiazines may be of particular value in treating patients who experience
delayed nausea and vomiting (postacute phase symptoms) on cisplatin
regimens.[5]
As with other dopaminergic antagonists, the most common side effects of
prochlorperazine are EPRs (acute dystonias, akathisias,
neuroleptic malignant syndrome [uncommon], and rarely, akinesias and
dyskinesias), and sedation. Marked hypotension may also result if IV
prochlorperazine is administered rapidly at high doses. Administration over at
least 30 minutes appears adequate to prevent hypotensive episodes.[6-8]
Butyrophenones
Droperidol and haloperidol
These two drugs represent another class of dopaminergic (D2 subtype) receptor
antagonists that are structurally and pharmacologically similar to the
phenothiazines. While droperidol is used primarily as an adjunct to anesthesia
induction, haloperidol is indicated as a neuroleptic antipsychotic drug;
however, both agents have potent antiemetic activity. Droperidol is
administered IM or IV, typically from 1 to 2.5 mg every
2 to 6 hours, but higher doses (up to 10 mg) have been safely given.[9,10]
Haloperidol is administered IM, IV, or orally,
typically from 1 to 4 mg every 2 to 6 hours.[11] Both agents may produce
EPRs, akathisia, hypotension, and sedation.
Dopamine 2 Antagonists
Metoclopramide
Metoclopramide is a substituted benzamide, which, prior to the introduction of serotonin (5-HT3)
receptor antagonists, was considered the most effective single antiemetic agent
against highly emetogenic chemotherapy such as cisplatin. Although
metoclopramide is a competitive antagonist at dopaminergic (D2) receptors, it
is most effective against acute vomiting when given IV at high doses
(e.g., 0.5–3 mg/kg/dose), probably because it is a weak competitive antagonist
(relative to other serotonin antagonists) at 5-HT3 receptors. It may act on
the CTZ and the periphery. Metoclopramide also increases lower esophageal
sphincter pressure and enhances the rate of gastric emptying, which may factor
into its overall antiemetic effect. It can be administered IV at
the U.S. Food and Drug Administration (FDA)–approved dose of 1 to 2 mg/kg every 2 hours (or less frequently) for 3
to 5 doses. Metoclopramide has also been safely given by IV bolus
injection at higher single doses (up to 6 mg/kg) and by continuous IV
infusion, with or without a loading bolus dose, with efficacy comparable to
multiple intermittent dosing schedules.[12-14] Metoclopramide is associated
with akathisia and dystonic extrapyramidal effects, with the latter seen more
commonly in persons younger than 30 years, and the former seen more
frequently in patients older than 30 years. Diphenhydramine, benztropine
mesylate, and trihexyphenidyl are commonly used prophylactically or
therapeutically to pharmacologically antagonize EPRs.[6,15] While cogwheeling rigidity, acute dystonia, and tremor are
responsive to anticholinergic medications, akathisia, the subjective sense of
restlessness or inability to sit still, is best treated by (1) switching to a
lower potency neuroleptic for emesis, if possible; (2) lowering the dose; or (3)
adding a benzodiazepine (i.e., lorazepam) or beta blocker (i.e., propranolol).
5-HT3 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 nausea and vomiting by preventing serotonin, which is released from
enterochromaffin cells in the gastrointestinal (GI) mucosa, from initiating afferent
transmission to the CNS via vagal and spinal sympathetic nerves.[16] The 5-HT3
antagonists may also block serotonin stimulation at the CTZ and other CNS
structures.
Ondansetron
Several studies have demonstrated that ondansetron produces an antiemetic
response that equals or is superior to high doses of metoclopramide, but
ondansetron has a superior toxicity profile compared with dopaminergic antagonist
agents.[17-23] Ondansetron (0.15 mg/kg) is given IV 15 to 30
minutes prior to chemotherapy and is repeated every 4 hours for two additional
doses. Alternatively, for patients older than 18 years, a large
multicenter study determined that a single 32-mg dose of ondansetron is more
effective in treating cisplatin-induced nausea and vomiting than a single 8-mg
dose, and is as effective as the standard regimen of three doses at 0.15 mg/kg given every 4 hours starting 30 minutes before chemotherapy.[24] A single-center retrospective chart review has reported ondansetron-loading doses of 16 mg/m² (maximum, 24 mg) IV to be safe in infants, children, and adolescents.[25]
Currently, the oral and injectable ondansetron formulations are approved for
use without dosage modification in patients older than 4 years,
including the elderly and patients with renal insufficiency. Oral ondansetron
is given 3 times daily starting 30 minutes before chemotherapy and continuing
for up to 2 days after chemotherapy is completed. Patients older than 12 years should receive 4 mg per dose. Ondansetron is not approved for use in
children younger than 4 years. Ondansetron clearance is diminished in patients
with severe hepatic insufficiency; therefore, such patients should receive a
single injectable or oral dose no greater than 8 mg. There is currently no
information available evaluating the safety of repeated daily ondansetron doses
in patients with hepatic insufficiency.
Other effective dosing schedules, such as a continuous IV infusion
(e.g., 1 mg/hr for 24 hours) or oral administration have also been
evaluated.[24] The major adverse effects include headache (which can be
treated with mild analgesics), constipation or diarrhea, fatigue, dry mouth,
and transient asymptomatic elevations in liver function tests (alanine [ALT]
and aspartate [AST] transaminases), which may be related to concurrent
cisplatin administration.[26] Ondansetron has been etiologically implicated in
a few case studies involving thrombocytopenia, renal insufficiency, and
thrombotic events.[27] In addition, a few case reports have implicated
ondansetron in causing EPRs. However, it is not clear in some cases whether
the events described were in fact EPRs, and in other
reports the evidence is confounded by concurrent use of other agents that are
known to produce EPRs. Nevertheless, the greatest advantage of serotonin
receptor antagonists over dopaminergic receptor antagonists is that they have
fewer adverse effects.
Despite prophylaxis with ondansetron, many patients receiving doxorubicin, cisplatin, or carboplatin will experience acute and delayed-phase nausea and vomiting.[28] A randomized, double-blind, placebo-controlled trial suggests that the addition of aprepitant, a neurokinin-1 (NK1) antagonist, may mitigate nausea and vomiting.[29] The optimal dose of aprepitant may be 125 mg on day 1 followed by 80 mg on days 2 to 5.[30]
Granisetron
Granisetron has demonstrated efficacy in preventing and controlling nausea and
vomiting at a broad range of doses (e.g., 10–80 µg/kg and empirically, 3
mg per dose). In the United States, granisetron injection and oral tablets are
approved for initial and repeat prophylaxis for patients receiving emetogenic
chemotherapy, including high-dose cisplatin. Granisetron is pharmacologically
and pharmacokinetically distinct from ondansetron; however, clinically it
appears equally efficacious and equally safe.[31-33] Both granisetron
formulations are given before chemotherapy, as either a single IV dose
of 10 µg/kg (0.01 mg/kg) or 1 mg orally every 12 hours.
Both granisetron formulations and ondansetron injection share the same
indication against highly emetogenic chemotherapy. In contrast, the oral
ondansetron formulation has been approved only for use against nausea and
vomiting associated with moderately emetogenic chemotherapy.
Currently, granisetron injection is approved for use without dosage
modification in patients older than 2 years, including the elderly and
patients with hepatic and renal insufficiency. Oral granisetron has not yet
been approved for use in pediatric patients.
Dolasetron
Both oral and injection formulations are indicated for the prevention of nausea
and vomiting associated with moderately emetogenic cancer chemotherapy
including initial and repeat courses. Oral dolasetron should be dosed as 100
mg within 1 hour before chemotherapy. Dolasetron should be given IV or orally at 1.8
mg/kg as a single dose approximately 30 minutes before chemotherapy.
The effectiveness of oral dolasetron in the prevention of chemotherapy-induced
nausea and vomiting has been proven in a large randomized, double-blind,
comparative trial of 399 patients.[34] Oral dolasetron was administered in the
range of 25 to 200 mg 1 hour prior to chemotherapy. The other study arm
consisted of oral ondansetron (8 mg) administered 1.5 hours before chemotherapy
and every 8 hours after, for a total of 3 doses. Complete response (CR) rates
improved with increasing doses of dolasetron. Both dolasetron 200 mg and
ondansetron had significantly higher CR rates as compared with
dolasetron 25 mg or 50 mg. (CR was defined as no emetic
episodes and no use of escape antiemetic medications.) Dolasetron injection
has also been proven effective in the prevention of chemotherapy-induced nausea
and vomiting.[35]
Palonosetron
Palonosetron is a new 5-HT3 receptor antagonist (second generation) that has antiemetic activity at both central and gastrointestinal sites. In comparison to the older 5-HT3 receptor antagonists, it has a higher binding affinity to the 5-HT3 receptors, a higher potency, a significantly longer half-life (approximately 40 hours, four to five times longer than that of dolasetron, granisetron, or ondansetron), and an excellent safety profile.[36] A dose-finding study demonstrated that the effective dose was 0.25 mg or higher.[36] In two large studies of patients receiving moderately emetogenic chemotherapy, CR (no emesis, no rescue) was significantly improved in the acute and the delayed period for patients who received 0.25 mg of palonosetron alone compared with either ondansetron or dolasetron alone.[37,38] 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,[39] 650 patients receiving highly emetogenic chemotherapy (cisplatin ≥60 mg/m2) also received either dexamethasone and one of two doses of palonosetron (0.25 mg or 0.75 mg) or dexamethasone and ondansetron (32 mg). Single-dose palonosetron was as effective as ondansetron in preventing acute chemotherapy-induced nausea and vomiting with dexamethasone pretreatment; it was significantly more effective than ondansetron throughout the 5-day postchemotherapy period. In an analysis of the patients in the above studies who received repeated cycles of chemotherapy, one author [40] reported that the CR rates for both acute and delayed chemotherapy-induced nausea and vomiting were maintained with single IV doses of palonosetron without concomitant corticosteroids. These data have been presented in abstract form only and will require further review. Based on the above studies, palonosetron was approved by the FDA in July 2003 for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy; and for the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.
Comparison of agents
Clinicians should note that studies suggest that there are no major
differences in efficacy or toxicity of the three first-generation 5-HT3 receptor antagonists
(dolasetron, granisetron, ondansetron) in the treatment of chemotherapy-induced
acute nausea and vomiting. These three agents are equivalent in efficacy and
toxicity when used in appropriate doses.[41-44]
Although these agents have been shown to be effective in the first 24 hours postchemotherapy (acute phase), they have not been demonstrated to be effective in days 2 to 5 postchemotherapy (delayed phase).[45,46,28]
Palonosetron, the second-generation 5-HT3 receptor antagonist, has been approved for the control of delayed emesis for patients receiving moderately emetogenic chemotherapy.[37,38]
Despite the use of both first-generation and second-generation 5-HT3 receptor antagonists, the control of acute chemotherapy-induced nausea and vomiting, and especially delayed nausea and vomiting, is suboptimal and there is considerable opportunity for improvement with either the addition or substitution of new agents in current regimens.[45,46,28,47]
Substance P Antagonists (NK-1 Receptor Antagonists)
The initial clinical studies using the NK-1 receptor antagonists [48-51] demonstrated that the addition of an NK-1 receptor antagonist (CP-122,721, CJ-11,794, MK-0869 [aprepitant]) to a 5-HT3 receptor antagonist plus dexamethasone prior to cisplatin chemotherapy improved the control of acute emesis compared to 5-HT3 plus dexamethasone, and improved the control of delayed emesis compared with placebo. In addition, as a single agent, MK-0869 (aprepitant) had a similar effect on cisplatin-induced acute emesis as ondansetron but was superior in the control of delayed emesis. Subsequent studies [52,53] showed that the combination of aprepitant and dexamethasone was similar to a 5-HT3 receptor antagonist plus dexamethasone in controlling acute emesis but was inferior in controlling acute emesis compared with triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone). These studies also confirmed the improvement of delayed emesis with the use of aprepitant compared with placebo. Two studies [30,54] have also shown an improvement in cisplatin-induced delayed emesis with the combination of aprepitant and dexamethasone compared with dexamethasone alone, with the improvement maintained over repeat cycles of cisplatin chemotherapy.
In two randomized, double-blind, parallel, multicenter, controlled studies (520 patients in each study), patients received cisplatin (≥70 mg/m2) and were randomized to receive either standard therapy of a 5-HT3 receptor antagonist (ondansetron) and dexamethasone prechemotherapy and dexamethasone postchemotherapy (days 2–4) or standard therapy plus aprepitant prechemotherapy and on days 2 and 3 postchemotherapy.[55,29] The CR (no emesis, no rescue) of the aprepitant group in both studies was significantly higher in both the acute period (83%–89%) and the delayed period (68%–75%), compared with the CR of the standard therapy group in the acute period (68%–78%) and delayed period (47%–56%). Nausea was improved in the aprepitant group for some, but not all of the various specific measures of nausea.[29] The studies discussed above formed the basis for the approval of aprepitant by the FDA in March 2003. In combination with other antiemetics, aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. An additional study confirmed the efficacy of aprepitant in the delayed period, when it was compared with ondansetron.[56]
All of the initial studies using aprepitant have been conducted in patients receiving highly emetogenic chemotherapy, such as cisplatin-based chemotherapy regimens. Subsequently, one group [57] presented a study on the use of aprepitant in 862 breast cancer patients receiving moderately emetogenic chemotherapy (i.e., cyclosphamide, doxorubicin). Two regimens were compared. Because the chemotherapy was moderately emetogenic, steroids were omitted from both arms, as illustrated in Table 2, Comparison of Aprepitant and Standard Regimens.
Table 2. Comparison of Aprepitant and Standard Regimens
Regimen
|
Day 1
|
Days 2 and 3
|
bid = twice a day.
|
Aprepitant |
Prechemotherapy: aprepitant (125 mg), ondansetron (8 mg), dexamethasone (12 mg) |
Aprepitant (80 mg/d) |
After 8 h: ondansetron (8 mg) |
Standard |
Prechemotherapy: ondansetron (8 mg), dexamethasone (20 mg) |
Ondansetron (8 mg bid) |
After 8 h: ondansetron (8 mg) |
There was a significant improvement in complete response (no emesis, no rescue) in the 24 hours after chemotherapy in the patients receiving aprepitant; however, there was no significant improvement in complete response on days 2 to 5 in the postchemotherapy period when aprepitant alone was compared with ondansetron alone. The overall (days 1–5) complete response was significantly improved for the aprepitant-containing regimen, most likely because of the improvement in the first 24 hours. The control of nausea in moderately emetogenic chemotherapy was not improved with the use of aprepitant without steroids on days 2 and 3 postchemotherapy. The role of aprepitant in moderately emetogenic chemotherapy remains unclear. These results were consistent for multiple cycles of chemotherapy.[58] One open-label study demonstrated that in the 5 days postchemotherapy, aprepitant in combination with palonosetron and dexamethasone is safe and highly effective in preventing chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy.[59]
Corticosteroids
Steroids are sometimes used as single agents against mild to moderately
emetogenic chemotherapy, but are more often used in antiemetic drug
combinations.[60-62] Their antiemetic mechanism of action is not fully
understood, but they may affect prostaglandin activity in the brain.
Clinically, steroids quantitatively decrease or eliminate episodes of nausea
and vomiting and may improve patients’ mood, thus producing a subjective sense
of well-being or euphoria (although they also can cause depression and
anxiety). In combination with high-dose metoclopramide, steroids may mitigate
adverse effects, such as the frequency of diarrheal episodes.
Steroids are often given IV before chemotherapy and may or may not
be repeated. Dosages and administration schedules are selected empirically.
Dexamethasone is often the treatment of choice in treating nausea and vomiting
in patients receiving radiation to the brain, as it also reduces cerebral
edema. It is administered orally, IM, or IV in the
dose range of 8 to 40 mg (pediatric dose: 0.25–0.5 mg/kg).[63-67]
Methylprednisolone is also administered orally, IM, or
IV at doses and schedules that vary from 40 to 500 mg every 6 to
12 hours for up to 20 doses.[62,68]
Dexamethasone is also used orally for delayed nausea and vomiting. Long-term
corticosteroid use, however, is inappropriate and may cause substantial
morbidity, including immunosuppression, proximal muscle weakness (especially
involving the thighs and upper arms), aseptic necrosis of the long bones,
cataract formation, hyperglycemia and exacerbation of preexisting diabetes or
escalation of subclinical diabetes to clinical pathology, adrenal suppression
with hypocortisolism, lethargy, weight gain, GI irritation, insomnia, anxiety,
mood changes, and psychosis. A study that examined chemotherapy in a group of patients with ovarian cancer found that short-term use of glucocorticoids as antiemetics had no negative effects on outcomes (i.e., overall survival, efficacy of chemotherapy).[69] As had previously been shown with metoclopramide,
numerous studies have demonstrated that dexamethasone potentiates the
antiemetic properties of 5-HT3 blocking agents.[70-74] If given
IV, dexamethasone should be given over 10 to 15 minutes, since rapid
administration may cause sensations of generalized warmth, pharyngeal tingling
or burning, or acute transient perineal and/or rectal pain.[66,75-77]
Prednisone and adrenocorticotropic hormone (ACTH) given concomitantly with
other active antiemetic agents have also demonstrated efficacy against
cisplatin-containing chemotherapy during the acute phase (within 24 hours
after receiving chemotherapy).[78-80] In a double-blind randomized study of
metoclopramide and dexamethasone with or without 1 mg of ACTH, patients
receiving ACTH prophylaxis for cisplatin-containing chemotherapy experienced
a significantly decreased incidence and severity of delayed emesis for up to
72 hours after treatment.[80]
Cannabinoids
Cannabinoids presumably target higher CNS structures to prevent nausea and
vomiting.[81] Dronabinol (delta-9-tetrahydrocannabinol) is one of the
psychoactive substances present in crude marijuana. Because of cultural and
societal constraints and a low therapeutic index at clinically useful dosages,
cannabinoids are often not among agents that are first selected for clinical
use, but may be accepted and useful in selected patients.[82] Dronabinol is
administered orally at 5 to 15 mg/m2, 1 to 3 hours before chemotherapy, then
every 2 to 4 hours for up to 6 doses/day.[83-85]
Adverse effects experienced along with the pharmacologic and psychogenic
effects of cannabinoids include the following:
- Acute withdrawal syndrome.
- Sedation.
- Dry mouth.
- Orthostatic hypotension.
- Dizziness.
- Ataxia.
Dronabinol
produces the following effects on the CNS at minimally effective dosages:[86-89]
- Euphoria or dysphoria.
- Feelings of detachment, depression, anxiety, paranoia, and panic.
- Decreased cognitive function.
- Memory loss.
- Increased tendencies toward impulsive and compulsive behaviors.
- Altered perceptions such as a distorted sense of time.
- Other sensory distortions.
- Hallucinations.
- Psychotic organic brain syndrome (rarely).
Cardiovascular adverse effects
typically manifest at dosages somewhat greater than those recommended for
antiemetic effect and include tachycardia, vasodilation with variable effects
on blood pressure, orthostatic symptoms, and decreased body temperature. With
chronic administration, tolerance to cardiovascular and subjective effects may
occur within days to weeks after treatment onset.[81]
Benzodiazepines
Benzodiazepines such as lorazepam, midazolam, and alprazolam, have become
recognized as valuable adjuncts in the prevention and treatment of anxiety and
anticipatory nausea and vomiting symptoms associated with chemotherapy,
especially with the highly emetogenic regimens given to children.[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.[93]
Benzodiazepines presumably act on higher CNS structures, the brainstem, and
spinal cord, and they produce anxiolytic, sedative, and anterograde amnesic
effects. In addition, they markedly decrease the severity of EPRs, especially
akathisia, associated with dopaminergic receptor antagonist antiemetics.
Lorazepam
Lorazepam may be administered orally, IM, IV, and sublingually.
Dosages range from 0.5 to 3 mg (alternatively, 0.025–0.05 mg/kg, or 1.5
mg/m2, but ≤4 mg per dose) in adults and 0.03 to 0.05 mg/kg in
children every 6 to 12 hours.[90,94-96] Midazolam produces mild-to-marked
sedation for 1 to 4.5 hours at doses equal to 0.04 mg/kg given IV
over 3 to 5 minutes.[97,98] Alprazolam has been shown to be effective when
given in combination with metoclopramide and methylprednisolone.[99]
The adverse effects of benzodiazepine include sedation, perceptual
disturbances, disorders of micturition and/or defecation, visual disturbances,
hypotension, anterograde amnesia, psychological dependence, confusion, ataxia,
and depressed mental acuity with intoxication.[100]
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.[101] Common side effects are sedation and weight gain,[102,103] as well
as an association with the onset of diabetes mellitus.[104] Olanzapine's activity at multiple receptors, particularly at the D2 and 5-HT3 receptors that appear to be involved in nausea and emesis, suggests that it may have significant antiemetic properties.
There have been case reports on the use of olanzapine as an antiemetic.[105-109] These case reports prompted a phase I study in which olanzapine was used for the prevention of delayed emesis in cancer patients receiving their first cycle of chemotherapy consisting of cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.[110] The protocol was completed by 15 patients, and no grade 4 toxicities were seen. The maximum tolerated dose was 5 mg per day for 2 days prior to chemotherapy and 10 mg per day for 7 days postchemotherapy. Based on these data, olanzapine appeared to be a safe and effective agent for the prevention of delayed emesis in chemotherapy-naive cancer patients receiving cyclophosphamide, doxorubicin, cisplatin, and/or irinotecan.
Using the maximum tolerated dose of olanzapine in the phase I trial, a phase II trial was performed for the prevention of chemotherapy-induced nausea and vomiting in patients receiving their first course of either highly emetogenic or moderately emetogenic chemotherapy. Olanzapine was added to granisetron and dexamethasone prechemotherapy and to dexamethasone postchemotherapy. CR (no emesis, no rescue) was 100% for the acute period (24 hours postchemotherapy), 80% for the delayed period (days 2–5 postchemotherapy), and 80% for the overall period (0–120 hours postchemotherapy) in ten patients receiving highly emetogenic chemotherapy (cisplatin, ≥70 mg/m2). CR was also 100% for the acute period, 85% for the delayed period, and 85% for the overall period in 20 patients receiving moderately emetogenic chemotherapy (doxorubicin, ≥50 mg/m2). Nausea was very well controlled in the patients receiving highly emetogenic chemotherapy, with no patient having nausea (0 on a scale of 0–10, M. D. Anderson Symptom Inventory [MDASI]) in the acute or delayed periods. Nausea was also well controlled in patients receiving moderately emetogenic chemotherapy, with no nausea in 85% of patients in the acute period and in 65% in the delayed and overall periods. There were no grade 3 or 4 toxicities. Based on these data, olanzapine appeared to be safe (sedation was the only dose-limiting toxicity) and effective in controlling acute and delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic and moderately emetogenic chemotherapy.[111]
Management of Chemotherapy-induced Nausea and Vomiting
Current guidelines [112,113] recommend that prechemotherapy management of chemotherapy-induced nausea and vomiting (CINV) be based on the emetogenic potential of the chemotherapy agent(s) selected. For patients receiving regimens with high emetogenic potential, the combination of a 5-HT3 receptor antagonist, aprepitant, and dexamethasone is recommended prechemotherapy; lorazepam may also be used. Aprepitant and dexamethasone are recommended postchemotherapy for the prevention of delayed emesis.
For patients receiving moderately emetogenic chemotherapy, the combination of a 5-HT3 receptor antagonist and dexamethasone should be used prechemotherapy, with or without lorazepam. Patients receiving the combination of an anthracycline and cyclophosphamide and select patients receiving certain other agents of moderate emetic risk, such as cisplatin (<50 mg/m2) or doxorubicin, should also receive aprepitant. Postchemotherapy, a 5-HT3 receptor antagonist, dexamethasone, or both are recommended for the prevention of delayed emesis.
For regimens with low emetogenic potential, dexamethasone is recommended with or without lorazepam. For regimens with minimal emetogenic risk, no prophylaxis is suggested.[112,113]
Antiemetic guidelines [112,113] 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.[45]
Clinicians and other health care professionals who are involved in administering chemotherapy should be aware that studies have strongly suggested that patients experience more acute and delayed chemotherapy-induced nausea and vomiting than is perceived by practitioners.[114,45,115] One study suggested that patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea.[116] In addition, the current and new agents have been used as prophylaxis for acute and delayed chemotherapy-induced nausea and vomiting and have not been studied for use in established chemotherapy-induced nausea and vomiting.[45,46] One study reported the effective use of intravenous palonosetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy.[117]
Pre- and postchemotherapy recommendations by emetogenic potential are summarized in Table 3, Antiemetic Recommendations by Emetic-Risk Categories.
Table 3. Antiemetic Recommendations by Emetic Risk Categoriesa
Emetic Risk Category
|
ASCO Guidelines
|
NCCN Guidelines
|
High (>90%) risk |
Three-drug combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant recommended prechemotherapy. |
Prechemotherapy, a 5-HT3 receptor antagonist (ondansetron, granisetron, dolasetron, or palonosetronb), dexamethasone (12 mg), and aprepitant (125 mg) 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 recommended 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 recommended, with or without lorazepam on days 2–4. |
Moderate (30%–90%) risk |
For patients receiving an anthracycline and cyclophosphamide, the three-drug combination of a 5-HT3 receptor antagonist, dexamethasone, and aprepitant recommended prechemotherapy; single-agent aprepitant recommended on days 2 and 3 for prevention of delayed emesis. |
For patients receiving an anthracycline and cyclophosphamide and selected patients receiving other 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) recommended, with or without lorazepam, prechemotherapy; for other patients, aprepitant is not recommended. |
For patients receiving other chemotherapies of moderate emetic risk, the two-drug combination of a 5-HT3 receptor antagonist and dexamethasone recommended prechemotherapy; single-agent dexamethasone or a 5-HT3 receptor antagonist suggested 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, recommended, with or without lorazepam on days 2–4. |
Low (10%–30%) risk |
Dexamethasone (8 mg) suggested; no routine preventive use of antiemetics for delayed emesis suggested. |
Metoclopramide, with or without diphenhydramine; dexamethasone (12 mg); or prochlorperazine recommended, with or without lorazepam. |
Minimal (<10%) risk |
No antiemetic administered routinely pre- or postchemotherapy. |
No routine prophylaxis; consider using antiemetics listed under primary prophylaxis as treatment. |
ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network.
|
aAdapted from Navari.[118]
|
bOrder of listed antiemetics does not reflect preference.
|
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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.
[PUBMED Abstract]
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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.
[PUBMED Abstract]
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Navari RM: Overview of the updated antiemetic guidelines for chemotherapy-induced nausea and vomiting. Community Oncology 4 (4 Suppl 1): 3-11, 2007. Also available online 10. Last accessed May 7, 2009.
Nausea, Vomiting, Constipation, and Bowel Obstruction in Advanced Cancer
Frequency
Nausea and vomiting is a common symptom in patients with advanced cancer,
occurring in approximately 21% to 68% of these patients.[1,2] The underlying
pathophysiology and treatment differs somewhat from nausea related to radiation
treatment or chemotherapy. Chronic nausea can significantly impair a patient’s
quality of life.
Pathophysiology and Causes
Chronic nausea in the setting of advanced cancer is often multifactorial in
origin.[1-3] Medications, including some that are frequently prescribed in the
setting of advanced cancer, such as opioids, nonsteroidal anti-inflammatory
drugs, and selective serotonin reuptake inhibitor (SSRI) antidepressants may be
responsible. In the case of opioids, nausea frequently resolves spontaneously
a few days after initiation of treatment. In some cases, however, it may
persist. Nausea resulting from the accumulation of active opioid metabolites
(morphine-6-glucuronide) has been described,[4] and patients with impaired
renal function may be at increased risk. Opioids invariably produce
constipation if prophylactic measures are not taken (namely the use of a
regular laxative regimen) and constipation is one of the most common causes of
nausea in patients with advanced cancer.[5-8] Opioid-induced gastrointestinal (GI)
motility problems may compound the problem of diminished GI
motility that many patients experience as part of the anorexia-cachexia
syndrome of advanced cancer. The autonomic dysfunction that often accompanies
this syndrome results in decreased GI motility, early satiety,
and chronic nausea.[9-11] Other causes of chronic nausea in these patients
include raised intracranial pressure (from metastatic brain disease or primary
brain tumors), metabolic abnormalities such as hypercalcemia, hyponatremia and
uremia, dehydration, malignant bowel obstruction, gastroduodenal ulcers, and infections of the mouth, pharynx, or esophagus.[12]
Nausea, like many other symptoms, may have psychological undercurrents that
either exacerbate or induce chronic nausea.
Assessment
A comprehensive history that includes determining the frequency and
effectiveness of bowel movements and laxative therapy is essential. Concurrent
medications should be reviewed and the frequency and nature of nausea and
vomiting should be documented. Examination should, among others, attempt to
exclude bowel obstruction, fecal impaction, dehydration, and raised
intracranial pressure. History and physical examination are poor at
determining the extent of constipation.[5] A plain flat-plate x-ray of the
abdomen can be very useful to this end.[13] Surgical x-ray views of the
abdomen may be helpful if a bowel obstruction is suspected. Investigations to
determine blood levels of electrolytes, calcium and renal parameters may also
be helpful.
Management
Management centers on identifying the underlying causes, addressing these when
possible, and controlling the symptoms.[1,2] A basic working knowledge of the
emetic pathways and identification of possible underlying causes should guide
antiemetic selection. Multiple antiemetic regimens have been proposed for the
management of chronic nausea in the setting of advanced cancer. Prospective
studies comparing one regimen with another are lacking. Metoclopramide or
domperidone are generally recommended as first-line agents because they improve
GI motility and act on the chemoreceptor trigger zone (as a
result of their antidopaminergic properties).[14] Metoclopramide can be
administered orally or parenterally (subcutaneously or intravenously [IV]) at doses
of 10 mg, 4 times a day, or on an every-4-hour basis, depending on the severity of
the nausea. Rescue doses should also be ordered on an as-needed basis to
manage the episodic worsening of nausea that may occur. Extrapyramidal-related
adverse effects are a potential complication of these medications, but appear
to occur infrequently. Domperidone, which is currently unavailable in the
United States, is associated with fewer of these adverse effects.
Unfortunately, this drug is not available in a parenteral formulation.
Dimenhydrinate (Dramamine) or antihistamine agents may be used if a complete
bowel obstruction is suspected (in which case prokinetic agents are
contraindicated) or if patients are intolerant to other antiemetic agents.
Haloperidol, a potent antidopamine agent, may be considered if bowel
obstruction is the underlying problem.[15] The phenothiazine drugs are
sometimes used,[16] but the high incidence of adverse effects, such as somnolence
and anticholinergic-related effects (orthostatic hypotension and confusion),
limit their role. Chlorpromazine has modest antiemetic activity but a high
incidence of sedation, postural hypotension, and anticholinergic adverse
effects, while piperazine derivatives such as prochlorperazine are stronger
antiemetics but cause more extrapyramidal side effects. Hyoscine butylbromide,
on the other hand, can be useful for patients experiencing colic from complete
bowel obstruction.
A continuous parenteral infusion of metoclopramide, at doses of 60 to 120 mg/day, may be helpful for patients with intractable chronic nausea.[17] The
judicious use of corticosteroids such as dexamethasone in selected patients may be useful in conjunction with a more traditional antiemetic, although one study has suggested that dexamethasone was not better than placebo in patients who were not controlled with metoclopramide.[18] The
exact mechanism of action and the optimal dose of corticosteroids for this
indication are not known.
In contrast to radiation therapy- or chemotherapy-induced nausea, the role of
5-HT3 receptor antagonists (such as ondansetron) is not clear in the setting of
chronic nausea in advanced cancer, but appears to be limited to a small number
of highly selected cases, specifically those that have failed all other
treatments.[19]
A case series study has suggested an antiemetic effect for olanzapine (an atypical antipsychotic) in advanced cancer patients being treated with opioids who are complaining of apparent opiate-induced nausea. However, further study and comparison with standard management are required.[20]
The management of constipation can be divided into general interventions and
therapeutic measures.[21] The general interventions include the prevention of
constipation by initiating regular laxative regimens, particularly in patients
on opioid treatment, and where possible, the elimination of medical factors
that may be contributing to constipation (e.g., discontinuation of nonessential
constipating drugs). Prophylactic laxative regimens may consist of stool
softeners such as docusate and bowel stimulants such as sennosides.
Occasionally lactulose may be added. If necessary, a hyperosmolar laxative such as lactulose or polyethylene glycol may be added.[22] These regimens should be reviewed on a
regular basis and their doses adjusted, depending on the regularity of bowel
movements. High-fiber diets, while generally recommended, may be difficult for
patients with very advanced cancer. Bulk agents such as psyllium or cellulose
are unsuitable for patients with advanced cancer because the high fluid intake
required with these agents is often intolerable to patients.
(Refer to the PDQ summaries on Gastrointestinal Complications 11 and Pain 5 for further information on the management of constipation caused by opioids.)
Therapeutic interventions for the routine management of constipation may be
administered orally or rectally. Oral laxatives include bulk agents, osmotic
agents, contact cathartics, and agents for colonic lavage. Saline laxatives,
including sodium salts (sodium phosphate) and magnesium salts (magnesium
citrate) may be useful to treat established constipation. Sodium phosphates
are generally administered rectally as an enema, but oral solutions are also
available. Magnesium citrate is generally administered orally and can be
especially useful if the constipation is primarily in the proximal bowel. The
contact cathartic bisacodyl, available as a suppository, may also be useful for
treating established constipation. Once the constipation is cleared, the
background laxative regimen (e.g., sennoside and docusate) should be reviewed
with the view of optimizing it. The action of the saline and magnesium salts
is not physiological and regular, ongoing administration should be avoided.
Saline laxatives should be used with caution in patients with renal impairment
or cardiac failure. Mineral oil enemas are used occasionally and act as both
lubricants and stool softeners. They may interfere with the absorption of
fat-soluble vitamins, however, and there is a risk of lipoid pneumonia in
debilitated patients. The use of enemas and rectal suppositories is usually
limited to the acute, short-term management of more severe episodes of
constipation. Patients with neurogenic bowel problems (e.g., patients with
irreversible spinal cord compression), however, often require regular, ongoing
treatment with suppositories as part of their bowel care. The rectal route is
contraindicated in patients with mucosal integrity/bowel-wall compromise.
(Refer to the PDQ summary on Gastrointestinal Complications 11 for further information.)
There have been no adequate comparative studies between the
various laxatives to make evidence-based recommendations on which laxative
regimen is optimal. Patients with advanced cancer are at risk of becoming
constipated and generally require a regular bowel regimen, even if they are not
eating. This need is amplified when they are on opioid treatment. On occasion,
patients may present with a refractory narcotic bowel syndrome despite
aggressive bowel care. Methylnaltrexone, a quaternary derivative of naltrexone, is an opioid antagonist that does not cross the blood-brain barrier. Preliminary studies suggest that it may be effective when given subcutaneously in the management of opioid-associated constipation without causing opioid withdrawal.[23-25] Methylnaltrexone should be avoided in cases of bowel obstruction and suspected bowel obstruction. This has not been studied in children.
Malignant Bowel Obstruction
The initial approach to assessing and managing malignant bowel obstruction in
the advanced cancer patient involves determining whether the obstruction is
reversible or not, and whether the obstruction is partial or complete.[26-28]
Suitability for surgery such as resection or intestinal bypassing should be
assessed. Several medical options are available to improve the comfort of
patients with inoperable bowel obstructions.[29,30] Less aggressive surgical
procedures such as the insertion of a venting gastrostomy tube can provide
considerable relief. The creation of ostomies, where the obstruction is
complete and irreversible, may also provide relief. Nasogastric tubes may be
used temporarily until the obstruction resolves, but where the obstruction is
irreversible, other options such as the insertion of a gastrostomy tube should
be considered. Antiemetic agents with prokinetic properties are relatively
contraindicated in the presence of a complete obstruction, and alternative
agents such as an antihistamine or haloperidol may be required. Clinical
experience suggests that corticosteroids (e.g., dexamethasone at a starting
dose of 6–10 mg subcutaneously, 3–4 times a day) may be useful for malignant
bowel obstruction.[26,27] The optimal dose and duration of treatment has not
been clarified. Hydration and drugs such as opioids and antiemetics should be
administered via routes other than the oral route. The subcutaneous route can
be very convenient and effective for both hydration and opioid administration.
This route is as effective as IV administration, is less invasive, and
requires less maintenance than the IV route. Octreotide, a somatostatin
analog, can be useful at doses of 100 to 200 µg subcutaneously, 3 times
a day, for refractory obstruction.[26,27,31] In the United States, octreotide is often
administered as a continuous infusion. If the obstruction causes severe colic,
hyoscine butylbromide may be considered. The use of colonic endoluminal
stenting devices in selected patients is gaining increasing attention.[32,33]
References
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Pereira J, Bruera E: Chronic nausea. In: Bruera E, Higginson I, eds.: Cachexia-Anorexia in Cancer Patients. New York, NY: Oxford University Press, 1996, pp 23-37.
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Baines MJ: Nausea, vomiting, and intestinal obstruction. In: Fallon M, O'Neill B, eds.: ABC of Palliative Care. London: BMJ Books, 1998, pp 16-18.
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Stephenson J, Davies A: An assessment of aetiology-based guidelines for the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer 14 (4): 348-53, 2006.
[PUBMED Abstract]
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Hagen NA, Foley KM, Cerbone DJ, et al.: Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage 6 (3): 125-8, 1991.
[PUBMED Abstract]
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Bruera E, Suarez-Almazor M, Velasco A, et al.: The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 9 (8): 515-9, 1994.
[PUBMED Abstract]
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Derby S, Portenoy RK: Assessment and management of opioid-induced constipation. In: Portenoy RK, Bruera E, eds.: Topics in Palliative Care. Volume 1. New York, NY: Oxford University Press, 1997, pp 95-112.
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Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, et al.: Treatment of opioid-induced constipation with oral naloxone: a pilot study. Clin Pharmacol Ther 52 (1): 90-5, 1992.
[PUBMED Abstract]
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Sykes NP: Oral naloxone in opioid-associated constipation. Lancet 337 (8755): 1475, 1991.
[PUBMED Abstract]
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Bruera E, Catz Z, Hooper R, et al.: Chronic nausea and anorexia in advanced cancer patients: a possible role for autonomic dysfunction. J Pain Symptom Manage 2 (1): 19-21, 1987 Winter.
[PUBMED Abstract]
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Thomas JP, Shields R: Associated autonomic dysfunction and carcinoma of the pancreas. Br Med J 4 (726): 32, 1970.
[PUBMED Abstract]
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Schuffler MD, Baird HW, Fleming CR, et al.: Intestinal pseudo-obstruction as the presenting manifestation of small-cell carcinoma of the lung. A paraneoplastic neuropathy of the gastrointestinal tract. Ann Intern Med 98 (2): 129-34, 1983.
[PUBMED Abstract]
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Ripamonti C, Bruera E: Chronic nausea and vomiting. In: Ripamonti C, Bruera E, eds.: Gastrointestinal Symptoms in Advanced Cancer Patients . New York, NY: Oxford University Press, 2002, pp 169-174.
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Starreveld JS, Pols MA, Van Wijk HJ, et al.: The plain abdominal radiograph in the assessment of constipation. Z Gastroenterol 28 (7): 335-8, 1990.
[PUBMED Abstract]
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Bruera E, Seifert L, Watanabe S, et al.: Chronic nausea in advanced cancer patients: a retrospective assessment of a metoclopramide-based antiemetic regimen. J Pain Symptom Manage 11 (3): 147-53, 1996.
[PUBMED Abstract]
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Critchley P, Plach N, Grantham M, et al.: Efficacy of haloperidol in the treatment of nausea and vomiting in the palliative patient: a systematic review. J Pain Symptom Manage 22 (2): 631-4, 2001.
[PUBMED Abstract]
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Kennett A, Hardy J, Shah S, et al.: An open study of methotrimeprazine in the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer 13 (9): 715-21, 2005.
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Bruera E, Brenneis C, Michaud M, et al.: Continuous Sc infusion of metoclopramide for treatment of narcotic bowel syndrome. Cancer Treat Rep 71 (11): 1121-2, 1987.
[PUBMED Abstract]
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Bruera E, Moyano JR, Sala R, et al.: Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manage 28 (4): 381-8, 2004.
[PUBMED Abstract]
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Pereira J, Bruera E: Successful management of intractable nausea with ondansetron: a case study. J Palliat Care 12 (2): 47-50, 1996 Summer.
[PUBMED Abstract]
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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 Abstract]
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Mancini I, Bruera E: Constipation in advanced cancer patients. Support Care Cancer 6 (4): 356-64, 1998.
[PUBMED Abstract]
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Bosshard W, Dreher R, Schnegg JF, et al.: The treatment of chronic constipation in elderly people: an update. Drugs Aging 21 (14): 911-30, 2004.
[PUBMED Abstract]
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Portenoy RK, Thomas J, Moehl Boatwright ML, et al.: Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage 35 (5): 458-68, 2008.
[PUBMED Abstract]
-
Thomas J, Karver S, Cooney GA, et al.: Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 358 (22): 2332-43, 2008.
[PUBMED Abstract]
-
Foss JF: A review of the potential role of methylnaltrexone in opioid bowel dysfunction. Am J Surg 182 (5A Suppl): 19S-26S, 2001.
[PUBMED Abstract]
-
Mercadante S: Assessment and management of mechanical bowel obstruction. In: Portenoy RK, Bruera E, eds.: Topics in Palliative Care. Volume 1. New York, NY: Oxford University Press, 1997, pp. 113-30.
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Fainsinger RL: Integrating medical and surgical treatments in gastrointestinal, genitourinary, and biliary obstruction in patients with cancer. Hematol Oncol Clin North Am 10 (1): 173-88, 1996.
[PUBMED Abstract]
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Ripamonti CI, Easson AM, Gerdes H: Management of malignant bowel obstruction. Eur J Cancer 44 (8): 1105-15, 2008.
[PUBMED Abstract]
-
Davis MP, Nouneh C: Modern management of cancer-related intestinal obstruction. Curr Pain Headache Rep 5 (3): 257-64, 2001.
[PUBMED Abstract]
-
Ripamonti C, Twycross R, Baines M, et al.: Clinical-practice recommendations for the management of bowel obstruction in patients with end-stage cancer. Support Care Cancer 9 (4): 223-33, 2001.
[PUBMED Abstract]
-
Mangili G, Franchi M, Mariani A, et al.: Octreotide in the management of bowel obstruction in terminal ovarian cancer. Gynecol Oncol 61 (3): 345-8, 1996.
[PUBMED Abstract]
-
Harris GJ, Senagore AJ, Lavery IC, et al.: The management of neoplastic colorectal obstruction with colonic endolumenal stenting devices. Am J Surg 181 (6): 499-506, 2001.
[PUBMED Abstract]
-
Spinelli P, Mancini A: Use of self-expanding metal stents for palliation of rectosigmoid cancer. Gastrointest Endosc 53 (2): 203-6, 2001.
[PUBMED Abstract]
Nonpharmacologic Management of Nausea and Vomiting
Nonpharmacologic strategies are also used to manage nausea and vomiting.
These include dietary alterations, hypnosis, acupuncture, acupressure,[1] relaxation techniques, behavioral therapy, and guided imagery. (Refer to the PDQ summary on Acupuncture 12 for more information.) Guided imagery, hypnosis, and systematic desensitization as means to progressive muscle relaxation have been the most frequently studied treatments for anticipatory nausea and vomiting (ANV) and are the recommended treatments for this classically conditioned response. (Refer to the Treatment of ANV 13 section of this summary for more information.)
Electroacupuncture has a demonstrated benefit for acute vomiting but not for acute nausea. Acupressure appears to reduce the severity of acute nausea but has not been tested in a placebo-controlled trial. A review of the literature suggests the need for further studies of electroacupuncture in patients also receiving state-of-the-art antiemetic pharmacologic treatment, to investigate clinical usefulness.[2]
References
-
Dibble SL, Luce J, Cooper BA, et al.: Acupressure for chemotherapy-induced nausea and vomiting: a randomized clinical trial. Oncol Nurs Forum 34 (4): 813-20, 2007.
[PUBMED Abstract]
-
Ezzo J, Vickers A, Richardson MA, et al.: Acupuncture-point stimulation for chemotherapy-induced nausea and vomiting. J Clin Oncol 23 (28): 7188-98, 2005.
[PUBMED Abstract]
Radiation Therapy
Correlates
Patients receiving radiation to the gastrointestinal (GI) tract or brain have the greatest
potential for nausea/vomiting as a side effect. 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 chemotherapy trigger zone. Similar to chemotherapy, radiation dose factors
also play a role in determining the possible occurrence of nausea and vomiting.
In general, the higher the daily fractional dose and the greater the amount of
tissue that is irradiated, the higher the potential for nausea and vomiting.
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 nausea and vomiting. Total-body irradiation before bone marrow transplant,
for example, has a high probability of inducing nausea and vomiting as acute
side effects.
Prevalence
Nausea and vomiting 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 antagonists for total-body irradiation vary
from 50% to 90%.[2-4] The role of corticosteroids in combination with 5-HT3
antagonists has not been studied.
References
-
Kris MG, Hesketh PJ, Somerfield MR, et al.: American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24 (18): 2932-47, 2006.
[PUBMED Abstract]
-
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 Abstract]
-
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 Abstract]
-
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 Abstract]
Get More Information From NCI
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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.
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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.
Prevention of Acute/Delayed Emesis 17
Added text 18 to state that one study suggested patients who are highly expectant of experiencing nausea appear to experience more postchemotherapy nausea (cited Colagiuri et al. as reference 116). Questions or Comments About This Summary
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