Pathophysiology and prediction of chemotherapy-induced nausea and vomiting
- Paul J Hesketh, MD
Paul J Hesketh, MD
- Section Editor — Supportive Care
- Chair, Lahey Health Cancer Institute
- Director, Thoracic Oncology, Lahey Hospital and Medical Center
- Professor of Medicine, Tufts University School of Medicine
Few side effects of cancer treatment are more feared by the patient than nausea and vomiting. Although nausea and emesis (vomiting and/or retching) can also result from surgery, opiates, or radiotherapy, chemotherapy-induced nausea and vomiting (CINV) is potentially the most severe and most distressing. Although significant progress has been made with the development of a number of effective and well-tolerated antiemetic treatments, CINV remains an important adverse effect of treatment.
The types of emesis, its pathophysiology, and factors predictive for the development of CINV will be reviewed here. The characteristics of the available antiemetic drugs, the management of CINV, and a general approach to the patient are discussed separately. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults" and "Characteristics of antiemetic drugs" and "Approach to the adult with nausea and vomiting".)
TYPES OF EMESIS
Three distinct types of CINV have been defined: acute, delayed, and anticipatory. Recognizing the differences between these types of CINV has important implications for both prevention and management.
Acute emesis — Acute emesis is defined as emesis occurring during the first 24 hours after chemotherapy. In the absence of effective prophylaxis, it most commonly begins within one to two hours of chemotherapy and usually peaks in the first four to six hours. Acute emesis is the most widely studied manifestation of CINV.
Delayed emesis — Emesis occurring more than 24 hours after chemotherapy is classified as delayed. It is best characterized following treatment with high-dose cisplatin. In the absence of antiemetic prophylaxis, delayed emesis after cisplatin peaks at approximately 48 to 72 hours after therapy, then gradually subsides over the next two to three days . While the frequency and number of episodes of emesis may be less during the delayed period compared with acute emesis, the delayed form is less well controlled with current antiemetic medications . Delayed emesis occurs most frequently after cisplatin but can also occur following other agents, including carboplatin, cyclophosphamide, anthracyclines, and oxaliplatin [2,3], and after combinations, such as cyclophosphamide plus an anthracycline.
- Kris MG, Gralla RJ, Clark RA, et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985; 3:1379.
- Tavorath R, Hesketh PJ. Drug treatment of chemotherapy-induced delayed emesis. Drugs 1996; 52:639.
- Hesketh PJ, Sanz-Altamira P, Bushey J, Hesketh AM. Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. Support Care Cancer 2012; 20:1043.
- Morrow GR, Roscoe JA, Kirshner JJ, et al. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 1998; 6:244.
- Borison HL. Area postrema: chemoreceptor circumventricular organ of the medulla oblongata. Prog Neurobiol 1989; 32:351.
- Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol 1994; 15:301.
- Fukuda H, Koga T. Non-respiratory neurons in the Bötzinger complex exhibiting appropriate firing patterns to generate the emetic act in dogs. Neurosci Res 1992; 14:180.
- Koga T, Fukuda H. Neurons in the nucleus of the solitary tract mediating inputs from emetic vagal afferents and the area postrema to the pattern generator for the emetic act in dogs. Neurosci Res 1992; 14:166.
- Carpenter DO. Neural mechanisms of emesis. Can J Physiol Pharmacol 1990; 68:230.
- Miller AD, Wilson VJ. 'Vomiting center' reanalyzed: an electrical stimulation study. Brain Res 1983; 270:154.
- Mitchelson F. Pharmacological agents affecting emesis. A review (Part I). Drugs 1992; 43:295.
- Bountra C, Gale JD, Gardner CJ, et al. Towards understanding the aetiology and pathophysiology of the emetic reflex: novel approaches to antiemetic drugs. Oncology 1996; 53 Suppl 1:102.
- BORISON HL, WANG SC. Physiology and pharmacology of vomiting. Pharmacol Rev 1953; 5:193.
- Wang SC. Emetic and antiemetic drugs. In: Physiological pharmacology: A comprehensive treatise, Root WS, Hofmann FG (Eds), Academic Press, New York 1965. Vol Vol II, p.225.
- Leslie RA. Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus. Neurochem Int 1985; 7:191.
- Andrews PL, Rapeport WG, Sanger GJ. Neuropharmacology of emesis induced by anti-cancer therapy. Trends Pharmacol Sci 1988; 9:334.
- Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst 1991; 83:613.
- Saria A. The tachykinin NK1 receptor in the brain: pharmacology and putative functions. Eur J Pharmacol 1999; 375:51.
- Watson JW, Gonsalves SF, Fossa AA, et al. The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor. Br J Pharmacol 1995; 115:84.
- Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology (Williston Park) 2004; 18:9.
- Rudd JA, Andrews PLR. Mechanisms of acute, delayed, and anticipatory emesis induced by anticancer therapies. In: Management of nausea and vomiting in cancer and cancer treatment, Hesketh PJ (Ed), Jones and Bartlett Publishers, Sudbury 2005. p.15.
- Rojas C, Slusher BS. Pharmacological mechanisms of 5-HT₃ and tachykinin NK₁ receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur J Pharmacol 2012; 684:1.
- Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008; 358:2482.
- Janelsins MC, Tejani MA, Kamen C, et al. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert Opin Pharmacother 2013; 14:757.
- Zagon A, Totterdell S, Jones RS. Direct projections from the ventrolateral medulla oblongata to the limbic forebrain: anterograde and retrograde tract-tracing studies in the rat. J Comp Neurol 1994; 340:445.
- Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15:103.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
- Grunberg SM, Warr D, Gralla RJ, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity--state of the art. Support Care Cancer 2011; 19 Suppl 1:S43.
- Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011; 29:4189.
- Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21 Suppl 5:v232.
- Olver IN, Simon RM, Aisner J. Antiemetic studies: a methodological discussion. Cancer Treat Rep 1986; 70:555.
- Jordan NS, Schauer PK, Schauer A, et al. The effect of administration rate on cisplatin-induced emesis. J Clin Oncol 1985; 3:559.
- Hesketh PJ, Plagge P, Bryson JC. Single dose ondansetron for the prevention of acute cisplatin-induced emesis: Analysis of efficacy and prognostic factors. In: Mechanisms and Control of Emesis, Bianchi L, Grelot AD, Miller GL (Eds), John Libby Eurotext Ltd, 1992. p.235.
- Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model. Cancer 1989; 64:1117.
- Pater J, Slamet L, Zee B, et al. Inconsistency of prognostic factors for post-chemotherapy nausea and vomiting. Support Care Cancer 1994; 2:161.
- Olver IN. Antiemetic study design: desirable objectives, stratifications and analyses. Br J Cancer Suppl 1992; 19:S30.
- Morrow GR, Roscoe JA, Hickok JT, et al. Initial control of chemotherapy-induced nausea and vomiting in patient quality of life. Oncology (Williston Park) 1998; 12:32.
- Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002; 20:2805.
- Tremblay PB, Kaiser R, Sezer O, et al. Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J Clin Oncol 2003; 21:2147.
- Fallowfield LJ. Behavioural interventions and psychological aspects of care during chemotherapy. Eur J Cancer 1992; 28A Suppl 1:S39.
- Morrow GR. The effect of a susceptibility to motion sickness on the side effects of cancer chemotherapy. Cancer 1985; 55:2766.
- Molassiotis A, Stamataki Z, Kontopantelis E. Development and preliminary validation of a risk prediction model for chemotherapy-related nausea and vomiting. Support Care Cancer 2013; 21:2759.
- Dranitsaris G, Bouganim N, Milano C, et al. Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 2013; 11:14.
- Clemons M, Bouganim N, Smith S, et al. Risk Model-Guided Antiemetic Prophylaxis vs Physician's Choice in Patients Receiving Chemotherapy for Early-Stage Breast Cancer: A Randomized Clinical Trial. JAMA Oncol 2016; 2:225.
- Warr D, DeAngelis C, Chow E. Can Patient Risk Factors Outperform Antiemetic Guidelines?: Choosing Wisely. JAMA Oncol 2016; 2:232.