The approach to the treatment of nausea and vomiting in a cancer patient should begin with a complete assessment, including the frequency, duration, and intensity of the nausea/vomiting; associated activities; and whether anorexia or cachexia is present. It is important to determine whether the nausea and vomiting is related to treatment (chemotherapy, radiation) or is independent of cancer treatment. Nausea/vomiting unrelated to chemotherapy and/or radiation may have an etiology for which there is a specific and potentially successful intervention. Various national and international antiemetic guidelines have been developed for the prevention of chemotherapy- and radiotherapy-induced nausea and emesis. The antiemetics recommended in these guidelines (5-hydroxytryptamine type 3 receptor antagonists, neurokinin-1 receptor antagonists, dexamethasone) have significantly reduced emesis but not nausea. Recent randomized clinical trials have demonstrated that olanzapine may be an effective agent for the prevention and treatment of chemotherapy-induced nausea as well as emesis.
Introduction
The sensation of nausea and the act of vomiting are protective reflexes that rid the intestine and stomach of toxic substances. Nausea may be considered a prodromal phase to the act of vomiting[1-3]; however, nausea and emesis are not necessarily on a continuum, and one can experience nausea without emesis-or can have sudden emesis without nausea.
Vomiting consists of a pre-ejection phase, retching, and ejection, and is accompanied by shivering and salivation. Nausea is a subjective sick or queasy sensation, usually perceived as being in the stomach.[3] The experience of nausea is difficult to describe to another person. Nausea has been assumed to be the conscious awareness of unusual sensations in the “vomiting center” of the brainstem, although the existence of such a center and its relationship to nausea remain controversial.[3]
This article will discuss the approach to and management of both treatment-related and non–treatment-related nausea and vomiting in cancer patients.
Pathophysiology of Nausea/Vomiting and Its Relation to Pharmacology
Knowledge of the mechanisms that give rise to nausea and vomiting in humans is based on lesional studies in animals.[3,4] Nausea/vomiting is triggered when afferent impulses from the cerebral cortex, the chemoreceptor trigger zone (located in the medulla, in the area postrema, near the fourth ventricle[3,4]), the pharynx, and vagal afferent fibers of the gastrointestinal (GI) tract travel to the vomiting center (termed the “central pattern generator” by some authors, and thought to be located in the lateral reticular formation of the medulla). Efferent impulses then travel from the vomiting center to the abdominal muscles, salivation center, cranial nerves, and respiratory center, causing vomiting. Although the mechanisms of emesis are not well defined, investigations suggest that emesis may be primarily mediated through neurotransmitters in the GI tract and the central nervous system.[3]
It is thought that chemotherapeutic agents cause vomiting by activating neurotransmitter receptors located in the chemoreceptor trigger zone, the GI tract, and the vomiting center. The pharmacologic approach to the control of nausea and emesis in patients with cancer has been to identify the active neurotransmitters and their receptors in the central nervous system and the GI tract that mediate the afferent inputs to the vomiting center (Figure). Active neurochemical signaling of nausea and vomiting may be mediated by 5-hydroxytryptamine (5-HT, or serotonin), dopamine, substance P, acetylcholine, histamine, gamma-aminobutyric acid, and cannabinoids.[5] Agents that may block receptors for these neurotransmitters in the chemoreceptor trigger zone, the vomiting center, or the GI tract may be useful in preventing or controlling nausea and emesis (Table 1).
The study of the receptors that are illustrated in the Figure has guided the development of the antagonists to the serotonin and the substance P receptors, which have had relative success in controlling emesis. These receptors are located both in peripheral areas, such as the GI tract, and in the central nervous system. It is not clear whether the serotonin and/or the substance P receptors are important in the control of nausea. Other receptors, such as dopaminergic, histaminic, and muscarinic receptors, may be the dominant receptors in the control of nausea.[1,3,6,7]
There have been a large number of studies and clinical trials for the prevention of treatment-related (mainly chemotherapy-related) emesis in cancer patients, and these have led to the development of a number of antiemetics.[1,2] However, these same clinical trials have shown that most efforts to prevent treatment-related nausea have not been effective.[3,6,7] In addition, few clinical trials have resulted in the successful treatment of established nausea and emesis caused by chemotherapy or radiation.[1,6,7]
Assessment of Nausea/Emesis
Patients with nausea should be assessed with a visual analog scale (0 to 10, with 0 signifying no nausea and 10 maximum nausea). The frequency, time of day, and any associated activities (meals, medications, exertion) should be noted. Similar assessments and observations should be made for emesis to try to determine the severity and the context of the nausea and emesis.
The history taking should include an inquiry regarding any prescription or over-the-counter medications that may be responsible for the nausea/emesis.[8,9] Nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, antibiotics, opioid analgesics, and oral iron have the potential to cause nausea/emesis. Recent or remote treatment with chemotherapy and/or radiation therapy should also be noted.[1]
The physical examination should include a detailed assessment of the abdomen for abdominal pain or tenderness in order to elicit clues to a possible organic cause of the nausea/emesis-such as bowel obstruction, an inflammatory process, or gastroparesis. Any abdominal distention, abnormal bowel sounds, ascites, hepatomegaly, or splenomegaly should be noted.[8,9]
A detailed neurologic examination should be performed to determine the presence of focal neurologic signs or papilledema suggestive of elevated intracranial pressure or central nervous system metastases. Vertigo and nystagmus are typical symptoms of vestibular neuritis (labyrinthitis) and other causes of vestibular dysfunction.[8]
Finally, inquiries about weight loss, appetite, anorexia, and/or cachexia should be made in order to further assess the nature of the nausea and emesis and provide insights into their possible etiology.
Non–Treatment-Related Nausea/Emesis in Cancer Patients
There are many etiologies of nausea/emesis in cancer patients that are unrelated to treatment with chemotherapy or radiation. Table 2 lists the various causes of non–therapy-related nausea/emesis, along with treatments recommended in current guidelines.[10-12] The recommended interventions are based on literature reviews conducted by the various national and international guideline committees.[10-12]
Nausea/Emesis Related to Cancer Treatment
Prevention of chemotherapy-induced nausea and vomiting (CINV)
Table 3 lists the well-known types of CINV.[1,2] The antiemetics guidelines of the various national and international societies have very specific recommendations for the antiemetic agents that should be used to prevent CINV; these are based on the emetogenicity of the specific chemotherapeutic agent being given.[11,13] Table 4 lists the various pharmacologic agents recommended for the prevention of CINV. For patients receiving highly emetogenic chemotherapy, recommendations are to use a neurokinin-1 (NK1) receptor antagonist, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist, and dexamethasone; for patients receiving moderately emetogenic chemotherapy, a 5-HT3 receptor antagonist or dexamethasone are recommended.
The foregoing agents have been successful in preventing emesis in the majority of patients, but they have not been effective in preventing nausea.[1,2,6,7,14] It appears that neither the serotonin nor the substance P receptors may be important in mediating nausea. However, phase III studies of the addition of olanzapine to an antiemetic prophylactic regimen have demonstrated very good control of both emesis and nausea in patients receiving either moderately emetogenic or highly emetogenic chemotherapy.[14,15] Olanzapine is now recommended in various national and international guidelines for the prevention of CINV in patients receiving highly emetogenic chemotherapy.[11,13]
Although there have been a number of studies in the literature reporting on complementary and alternative therapies for the prevention of CINV, evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure, and other complementary or alternative therapies in this setting.[11,16]
Breakthrough CINV
Phenothiazines, metoclopramide, dexamethasone, or olanzapine may be effective in the treatment of breakthrough nausea and vomiting.[11] A 5-HT3 receptor antagonist may also be effective-unless a patient presents with nausea and vomiting that developed following the use of a 5-HT3 receptor antagonist as prophylaxis for chemotherapy- or radiotherapy-induced emesis. It is very unlikely that breakthrough nausea and vomiting will respond to an agent in the same drug class as one that has been used unsuccessfully for prophylaxis.
Patients who develop nausea or vomiting post-chemotherapy (days 1–5) despite adequate prophylaxis should be considered for treatment with a regimen of 3 days of oral or sublingual olanzapine or oral metoclopramide. A recently completed phase III study demonstrated that oral olanzapine (10 mg/d for 3 days) was significantly better than oral metoclopramide (10 mg TID for 3 days) at controlling both emesis and nausea in patients receiving highly emetogenic chemotherapy who developed breakthrough CINV despite guideline-directed prophylactic antiemetics.[17]
It is important to note that NK1 receptor antagonists have been approved as an additive agent along with a 5-HT3 receptor antagonist and dexamethasone for the prevention of CINV, but have not been studied and should not be used to treat breakthrough nausea and vomiting.
Refractory CINV
If a patient develops CINV during subsequent cycles of chemotherapy after antiemetic prophylaxis has been unsuccessful in controlling CINV in earlier cycles, a change in the prophylactic antiemetic regimen should be considered. If anxiety is thought to be a major factor in the CINV, a benzodiazepine such as lorazepam or alprazolam can be added to the prophylactic regimen. If the patient is receiving highly emetogenic chemotherapy, olanzapine (days 1–4) may be added to a prophylactic regimen of a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone,[11,14] or can be substituted for an NK1 receptor antagonist in combination with a 5-HT3 receptor antagonist and dexamethasone.[11,15] If the patient is receiving moderately emetogenic chemotherapy, an NK1 receptor antagonist may be added to an antiemetic regimen of palonosetron and dexamethasone.[11]
Anticipatory CINV
In order to prevent the occurrence of anticipatory CINV, patients should be counseled prior to the initial course of treatment concerning their expectations of CINV. Patients should be informed that very effective prophylactic antiemetic regimens will be used and that 70% to 75% of patients will have a complete response (ie, no emesis, no use of rescue medications). Patients’ risk factors for CINV (Table 5) should be carefully evaluated, and the most effective prophylactic antiemetic regimen for the patient’s specific type of chemotherapy should be used prior to the first course of chemotherapy in order to obtain optimum control of CINV during this first course. If CINV is effectively controlled during the first chemotherapy cycle, it is likely that the patient will have effective control during subsequent cycles of the same chemotherapy. If the patient has a poor experience with CINV in the first cycle, it may be more difficult to control CINV in subsequent chemotherapy cycles, and refractory and/or anticipatory CINV may occur. The use of anti-anxiety medications such as lorazepam or another benzodiazepine may be considered for excess anxiety prior to the first course of chemotherapy in order to obtain an optimal outcome and prevent anticipatory CINV. If anticipatory CINV occurs despite the use of prophylactic antiemetics, behavioral therapy can be considered.[18-20]
Multi-day chemotherapy and high-dose chemotherapy with bone marrow or stem cell transplantation (SCT)
The success of NK1 receptor antagonists along with 5-HT3 receptor antagonists and dexamethasone in preventing emesis in patients receiving single-day highly emetogenic chemotherapy[1,2] prompted the use of the NK1 receptor antagonist aprepitant combined with a 5-HT3 receptor antagonist and dexamethasone in patients receiving multi-day high-dose chemotherapy prior to SCT. A number of phase II and III studies have now reported on the use of aprepitant added to a 5-HT3 receptor antagonist and dexamethasone in patients receiving multi-day high-dose chemotherapy prior to autologous or allogeneic SCT.[21-24] As a result of these studies, the 2017 American Society of Clinical Oncology (ASCO) and the 2017 Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology antiemetic guidelines have recommended the use of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone as the preferred prophylaxis for patients receiving multi-day high-dose chemotherapy prior to autologous or allogeneic SCT.[11,13] However, while the recent studies mentioned[21-24] have demonstrated that the addition of aprepitant to a 5-HT3 receptor antagonist and dexamethasone resulted in improved control of emesis post chemotherapy, they did not demonstrate an improvement in nausea. The control of nausea remains a significant problem for patients, not only for those receiving multi-day high-dose chemotherapy, but also for those receiving single-day highly emetogenic chemotherapy. Neither 5-HT3 receptor antagonists, nor the NK1 receptor antagonists, appear to be effective antinausea agents in the post-chemotherapy period.[1,2,6,7,13-15]
KEY POINTS
- A complete assessment of nausea/emesis in a cancer patient should include documentation of the frequency, duration, and intensity of the nausea and/or vomiting, and associated activities; investigation into the possible etiology; and ascertainment of whether anorexia or cachexia is present.
- National/international antiemetic guidelines should be followed for the treatment of established nausea and vomiting and for the prevention of treatment-induced nausea and emesis.
- A number of neurokinin-1 receptor antagonists and 5-hydroxytryptamine type 3 receptor antagonists, along with dexamethasone, have proven effective at preventing chemotherapy-induced nausea and vomiting; however, none of these agents have been effective at preventing nausea. The addition of olanzapine to a prophylactic regimen has been shown to provide very good control of nausea as well as vomiting.
Radiotherapy-induced nausea/emesis
There have been few randomized controlled clinical trials that have studied the prevention or treatment of nausea/emesis associated with radiotherapy. Dennis and colleagues[25] performed a systematic review of radiotherapy-induced nausea and vomiting and found that the clinical trial designs varied considerably in the methodologies, endpoints, and outcome measures employed,[25] rendering it difficult to make definitive recommendations. Chiu and colleagues[26] have suggested that a short course of dexamethasone with or without a 5-HT3 receptor antagonist may be considered for prophylaxis of radiotherapy-induced nausea and emesis. The ASCO antiemetic guidelines[11] suggest dexamethasone plus a 5-HT3 receptor antagonist for patients who will undergo total body radiation and a 5-HT3 receptor antagonist alone for those receiving radiotherapy to the upper abdomen.
Chronic Nausea and Vomiting in Cancer Patients
A particularly difficult clinical problem in patients with cancer is chronic nausea/emesis that is unrelated to recent treatment with chemotherapy and/or radiation. Patients may have persistent nausea/emesis weeks after the completion of treatment, and often the etiology is not clear. These may be patients who are receiving palliative care or hospice care, and/or patients with large tumor burdens. The approach to these patients is currently largely empirical, based on personal experience and/or case reports, because the evidence base for treatment in this setting is minimal, consisting largely of poor-quality trials, uncontrolled trials, and case studies.[10-12] Table 6 lists agents that have been used in patients with chronic nausea/emesis with at least some, albeit limited, success.
Haloperidol and prochlorperazine act through dopamine receptors but have limited efficacy and have serious potential side effects, particularly in elderly patients.[12] A multi-institutional study followed patients in whom haloperidol was initiated for nausea/vomiting during routine clinical care; 3 out of 4 of these patients experienced “some benefit” within 48 hours, with one-third of the patients who experienced benefit having no adverse events.[27]
Dexamethasone may be effective for chronic nausea/emesis but should be used in the smallest possible dose for the shortest possible period of time due to its long-term toxicity.[1,8,9] Metoclopramide has been used with some success in some patients with chronic nausea/emesis, but its potential toxicity limits its use to lower doses (10 mg TID for up to 3 days).[1,2]
Olanzapine is an atypical antipsychotic that has been used successfully for the prevention of CINV.[14] It blocks multiple neurotransmitter receptors, including dopaminergic, serotonergic (5-HT2C, 5-HT3), catecholamine α1 adrenergic, muscarinic acetylcholine, and histamine receptors. While its specific mechanism of action in CINV is unknown, olanzapine has been shown to be effective for breakthrough CINV[17] and for the treatment of nausea and vomiting in palliative care.[12,28-30] However, it should be used with caution in elderly patients because it may cause short-term sedation.[14]
Behavioral approaches such as distraction or relaxation training utilizing muscle relaxation and guided imagery have not demonstrated consistent benefit to patients in palliative care.[8,9,12,31] A systematic review of complementary and alternative medicine approaches to symptom management at the end of life was unable to identify any large-scale trials of treatments for nausea and vomiting in terminally ill patients.[8,9,12,31] There are no randomized, double-blind, phase III clinical trials of nonpharmacologic approaches that demonstrate benefit in the palliative care setting.[8,9,12,31]
The recent MASCC guidelines for the management of nausea and vomiting in advanced cancer[12] suggest that the evidence base in this field is minimal, consisting largely of poor-quality trials or uncontrolled trials and case studies. The agents recommended in these guidelines for managing nausea and vomiting in advanced cancer are metoclopramide, haloperidol, levomepromazine, and olanzapine. For opioid-induced nausea and vomiting, no recommendation could be made.[12]
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
References:
1. Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;374:1356-67.
2. Navari RM. Management of chemotherapy-induced nausea and vomiting: focus on newer agents and new uses for older agents. Drugs. 2013;73:249-62.
3. Stern RM, Koch KL, Andrews PL. Nausea: mechanisms and management. New York: Oxford University Press; 2011.
4. Koga T, Fukuda H. Neurons in the nucleus of the solitary tract mediating inputs from vagal afferents and the area postrema in the pattern generator in the emetic act in dogs. Neurosci Res. 1992;14:366-79.
5. Bashashati M, McCallum RW. Neurochemical mechanisms and pharmacologic strategies in managing nausea and vomiting related to cyclic vomiting syndrome and other gastrointestinal disorders. Eur J Pharmacol. 2014;722:79-94.
6. Navari RM. Treatment of chemotherapy-induced nausea. Community Oncol. 2012;9:20-6.
7. Ng TL, Hutton B, Clemons M. Chemotherapy-induced nausea and vomiting: time for more emphasis on nausea? Oncologist. 2015;20:576-83.
8. Glare P, Miller J, Nikolova T, et al. Treating nausea and vomiting in palliative care: a review. Clin Intervent Aging. 2011;6:243-59.
9. Smith HS, Smith JM, Smith AR. An overview of nausea/vomiting in palliative medicine. Ann Palliat Med. 2012;1:103-14.
10. NCCN clinical practice guidelines in oncology. Palliative care. Version 1.2018; December 19, 2017. https://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf. Accessed February 7, 2018.
11. NCCN clinical practice guidelines in oncology. Antiemesis. Version 2.2017; March 28, 2017. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed February 7, 2018.
12. Walsh D, Davis D, Ripamonti C, et al. 2016 updated MASCC/ESMO consensus recommendations: management of nausea and vomiting in advanced cancer patients. Support Care Cancer. 2017;25:333-40.
13. Molassiotis A, Aapro M, Herrstedt J, et al. MASCC/ESMO antiemetic guidelines: introduction to the 2016 guideline update. Support Care Cancer. 2017;25:267-9.
14. Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016;375:134-42.
15. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol. 2011;9:188-95.
16. Thamlikitkul L, Srimuninnimit V, Akewanlop C, et al. Efficacy of ginger for prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving adriamycin-cyclophosphamide regimen: a randomized, double-blind, placebo-controlled, crossover study. Support Care Cancer. 2017;25:459-64.
17. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2013;21:1655-63.
18. Navari RM. Should behavioral therapy be used as the primary treatment to control anticipatory vomiting? HemOnc Today. May 10, 2016. https://www.healio.com/hematology-oncology/breast-cancer/news/print/hemonc-today/%7Be07f26de-fdd7-40cd-96e0-68a49a6ba56f%7D/increased-awareness-new-therapies-may-alleviate-pervasive-problem-of-cinv?page=6. Accessed February 9, 2018.
19. Navari RM. Cancer patients at high risk for chemotherapy-induced nausea and vomiting-prediction assessments/tools. Expert Rev Quality Cancer Care. 2017;2:102-8.
20. Kamen C, Mohamedtaki A, Tejani KC, et al. Anticipatory nausea and vomiting due to chemotherapy. Eur J Pharmacol. 2014;722:172-9.
21. Schmitt T, Goldschmidt H, Neben K, et al. Aprepitant, granisetron, and dexamethasone for prevention of chemotherapy-induced nausea and vomiting after high-dose melphalan in autologous transplantation for multiple myeloma: results of a randomized, placebo-controlled phase III trial. J Clin Oncol. 2014;32:3413-20.
22. Pielichowski W, Barzal J, Gawronski K, et al. A triple-drug combination to prevent nausea and vomiting following BEAM chemotherapy before autologous hematopoietic stem cell transplantation. Transpl Proc. 2011;43:3107-10.
23. Stiff PJ, Fox-Geiman MP, Kiley K, et al. Prevention of nausea and vomiting associated with stem cell transplant: results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow Transplant. 2013;19:49-55.
24. Svanberg A, Bergegård C. Addition of aprepitant to standard antiemetic regimen continued for 7 days after chemotherapy for stem cell transplantation provide significant reduction of vomiting. Oncology. 2015;89:31-6.
25. Dennis K, Rehana J, McGrath C, et al. A systematic review of methodologies, endpoints, and outcome measures in randomized trials of radiation therapy-induced nausea and vomiting. Support Care Cancer. 2017;25:2019-33.
26. Chiu N, Chiu L, Popovic M, et al. Latest advances in the management of radiation-induced pain flare, nausea and vomiting. Ann Palliat Med. 2016;5:50-7.
27. Digges M, Hussein A, Wilcock A, et al. Pharmacovigilance in hospice/palliative care: net effect of haloperidol for nausea and vomiting. J Palliat Med. 2018;21:37-43.
28. Prommer E. Olanzapine: palliative medicine update. Am J Hospice Palliat Med. 2012;30:75-82.
29. Jackson WC, Tavernier L. Olanzapine for intractable nausea in palliative care patients. J Palliat Med. 2003;6:251-5.
30. Kaneishi K, Kawabata M, Morita T. Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manage. 2012;44:604-7.
31. Momani TG, Berry DL. Integrative therapeutic approaches for the management and control of nausea in children undergoing cancer treatment: a systematic review of literature. J Pediatr Oncol Nursing. 2017;34:173-84.
