With his comprehensive review, Schwartzberg covers the major topics in antiemetic therapy, from the physiology of emesis to the available antiemetics. Meta-analyses concluded that 5-HT3 receptor antagonists improved control of emesis by an absolute 11% (cisplatin) to 17% (moderately emetogenic chemotherapy). Corticosteroids improved the control of emesis by 16%. Neurokinin (NK)-1 receptor antagonists reduced emesis above and beyond that achieved with a 5-HT3 receptor antagonist plus dexamethasone by another 21% for those receiving high-dose cisplatin and 17% in women receiving an anthracycline plus cyclophosphamide.
Although emesis was once rated by cancer patients to be the most troublesome side effect of chemotherapy, it has fallen further down the list after the introduction of doublet therapy. The results of 25 years of antiemetic research have been impressive, showing numerically large improvement with little in the way of adverse events.
1. Which patients should receive NK-1 receptor antagonists?
In the title of Schwartzberg's article is a question that has been only partially answered: "Which antiemetic for which therapy?" In other words, for which treatments do we need triple antiemetic therapy? Although aprepitant (Emend) represents a clear advance in antiemetic therapy, it is expensive, at an average wholesale price of approximately US $300. It is appropriate to ask which patients should receive this add-on antiemetic.
For women receiving an anthracycline plus cyclophosphamide or anyone receiving high-dose cisplatin, the answer from phase III trials seems clear: Use aprepitant. The guideline from the National Comprehensive Cancer Network extends the recommendation to "select patients receiving other chemotherapy of moderate emetic risk . . ." Carboplatin, cisplatin, irinotecan (Camptosar), and ifosfamide are included as examples. How one would select patients apart from a poor experience in a prior chemotherapy cycle is unclear. Prospective studies focusing on the frequency of emesis despite doublet therapy are needed.
2. Should factors other than chemotherapy type be used to choose antiemetic drugs?
Schwartzberg refers to interesting data on interpatient variation in the metabolism of 5-HT3 receptor antagonists. Receptor subtypes may also influence the antiemetic efficacy of the 5-HT3 receptor antagonists. These fields of study are still in their infancy, and it is unclear when, if ever, this information will be available to allow individualized therapy.
Age, gender, quality of life, and a number of other factors influence the likelihood of chemotherapy-induced nausea and vomiting. However, with the exception of establishing that anthracycline-plus-cyclophosphamide therapy is best categorized as highly emetogenic in females, these other factors have not been incorporated into recommendations for standard therapy. Apart from emesis with a previous cycle of chemotherapy, there is no prognostic factor that we should use to identify patients for more aggressive antiemetic prophylaxis than that recommended by guidelines.
3. Which if any dopamine receptor antagonists should be prescribed?
Standard clinical practice has included a take-home prescription for a dopamine receptor antagonist such as metoclopramide or prochlorperazine in modest doses. Placebo-controlled trials of these drugs in low doses are lacking. The demonstration of equivalence with 5-HT3 receptor antagonists in the delayed phase is faint praise, given that the administration of a 5-HT3 beyond 24 hours did not seem to have clinically important benefits in a recent meta-analysis. High-dose metoclopramide was certainly an effective antiemetic, but it is also a 5-HT3 receptor antagonist, and much of its antiemetic activity may be mediated by that receptor.
Trials of metopimazine demonstrate that this drug has antiemetic activity, but it is not available in most countries (including the United States). Although untested in randomized trials, a phase II study suggested that the atypical antipsychotic agent olanzapine (Zyprexa) is also an effective antiemetic. This does not prove the importance of dopamine receptor antagonism because olanzapine also binds to the site of muscarinic, alpha-1-adrenergic, and several 5-HT receptors; thus, its mechanism of antiemetic action remains unknown. For the moment, the best that we can say about the common practice of prescribing low-dose dopamine receptor antagonists is that they are generally well tolerated.
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