Faculty of Pharmacy
University of Montreal
Chemotherapy-induced nausea and vomiting (CINV) are significant side-effects of cancer treatments. Patients attending oncology clinics indicate that nausea and vomiting constitute their main concerns.(1,2) The consequences of nausea and vomiting are numerous and can be physical, physiological or psychological. They negatively impact on patients’ quality of life and have significant economic consequences. It is estimated that up to 15% of patients who should be treated with chemotherapy refuse it because of nausea and vomiting.(3) For patients who could benefit from chemotherapy, treatment interruption may lead to progression of the disease and may result in an increase in mortality and morbidity.(4)
Chemotherapy-induced emesis can be divided into three categories: acute, delayed and anticipatory. Acute nausea and vomiting is the most frequent and is generally associated with a high degree of severity. It occurs during the first 24 hours following the administration of chemotherapy. Delayed nausea and vomiting occurs one to five days after the administration of chemotherapy. It usually lasts longer but is less severe than acute nausea and vomiting. Anticipatory nausea and vomiting refers to a conditioned response that occurs before the chemotherapy, and may be triggered by an event related to a previous emesis experience that leads the patient to think that another emetic episode is about to occur.
The incidence and severity of emesis vary according to the type of chemotherapy. Chemotherapeutic treatments can be divided according to their emetogenic potential. Different groupings of chemotherapeutic agents have been proposed – one often used divides agents into highly, moderately or weakly emetogenic. Most classifications consider the emetic potential of agents when used alone, although in reality they are often used in combination. In such cases, the emetogenic potential of the combination is usually defined according to the emetic potential of the most emetogenic agent of the combination. To better take into consideration the additive emetogenic potential of combined agents, Hesketh et al proposed an algorithm to estimate the emetogenic potential of the combined drugs,(5) which has been adopted by a large number of oncology centres. Other factors can also influence the incidence of CINV.(6) Younger patients are more likely to have CINV than older patients. Patients with a history of chronic alcohol consumption usually experience less CINV, while patients with a history of motion sickness are at greater risk.
Antiemetic treatments currently available
Different types of agents are used to prevent chemotherapy-induced emesis (see Table 1). Most of these agents were not specifically developed for their antiemetic properties; their potential to control CINV is relatively limited and usually a better efficacy is achieved by using them in combination. The availability of the serotonin antagonists since the early 1990s has significantly improved the control of acute nausea and vomiting. Compared with other antiemetic categories, serotonin antagonists have shown significantly better emesis protection for patients receiving highly or moderately emetic chemotherapy. Serotonin antagonists have a relatively good safety profile and do not produce the dystonic reactions reported with the benzamide derivatives.
In their dose–response curves, serotonin antagonists reach a plateau relatively rapidly, so increasing their dosage does not necessarily lead to a corresponding increase in efficacy. Concomitant use of cortico-steroids has been shown to potentiate the efficacy of serotonin antagonists. For the control of delayed emesis, serotonin antagonists are not necessarily better than other antiemetics, such as corticosteroids.
Serotonin antagonists are generally more expensive than the other antiemetics available. Therefore from a cost-efficacy standpoint, it is recommended to use the serotonin antagonists as follows:(7)
- Reserve these agents for the prevention of emesis induced by highly or moderately emetogenic chemotherapies.
- Avoid use of highest recommended dosage.
- Use them in combination with a corticosteroid.
- Limit their use for a relatively short period of time (one to two days).
- Consider using an oral formulation instead of an injectable one.
For the control of delayed emesis, a combination of metoclopramide or alizapride with a corticosteroid could be more appropriate.
Antiemetics in development
With the use of serotonin antagonists, control of acute emesis has been improved, but control of delayed emesis remains troublesome. Other antiemetics are presently under clinical development. The most promising agents are the antagonists of the neurotransmitter “Substance P”, which exert their effects by binding to the neurokinin NK1 receptors. Aprepitant was recently licensed by the US FDA for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Results of initial studies with these agents in the control of cisplatin-induced emesis indicate that they are well tolerated and particularly effective for the control of delayed emesis.(8,9) In a study on the prevention of cisplatin-induced emesis, an NK1 antagonist was compared with a serotonin antagonist. Both treatments had comparable efficacy for controlling acute emesis, but the proportion of patients with a complete control of delayed emesis was superior with the NK1 antagonist (72% vs 30%; p=0.0005).(10) These agents are expected not to replace currently used antiemetics, but to be added to the existing armamentarium.
Achieving effective control of CINV is not an easy task, particularly with highly emetic chemotherapy. Fortunately, more effective antiemetics are now available and others will be launched in the near future. The newer agents are generally more expensive than the older antiemetics and can have a significant impact on the pharmacy budget, but when used appropriately they have a favourable cost-effectiveness profile.
The main focus in oncology is on tumour resorption, but from a patient perspective the impact of the cancer treatment on quality of life is, in many cases, as important. Control of CINV is generally considered as “supportive” care, but it should be one of the critical considerations when establishing an anticancer treatment. As much attention should be placed on the selection of the antiemetic treatment as on the selection of the chemotherapy.
- 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 1983;19:203-8.
- Griffin AM, Butow PN, Coates AS, et al. On the receiving end. V: Patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 1996;7:189-95.
- Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988;6:1746-52.
- Lindley CM, Bernard S, Fields SM. Incidence and duration of chemotherapy-induced nausea and vomiting in the outpatient oncology population. J Clin Oncol 1989;7:1142-9.
- Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997;15:103-9.
- Markman M. Progress in preventing chemotherapy-induced nausea and vomiting. Cleve Clin J Med 2002;69:609-17.
- Lachaine J, Laurier C. Cost-efficacy analysis of ondansetron regimens for control of emesis induced by noncisplatin, moderately emetogenic chemotherapy. Am J Health-Syst Pharm 2002;59:1837-46.
- Hesketh PJ. Potential role of the NK1 receptor antagonists in chemotherapy-induced nausea and vomiting. Support Care Cancer 2001;9:350-4.
- Herrstedt J. Potential new agents in the prophylaxis and treatment of chemotherapy-induced emesis. Eur J Cancer 2001;37:823-5.
- Cocquyt V, Van Belle S, Reinhardt RR, et al. Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis. Eur J Cancer 2001;37:835-42.