Antiemetic Therapy: Much Progress, Much More to be Done

July 1, 2007

A review of "Chemotherapy-Induced Nausea and Vomiting: Which Antiemetic for Which Therapy?"



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).[1] Corticosteroids improved the control of emesis by 16%.[2] 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[3] and 17% in women receiving an anthracycline plus cyclophosphamide.[4]

Although emesis was once rated by cancer patients to be the most troublesome side effect of chemotherapy,[5] it has fallen further down the list after the introduction of doublet therapy.[6] The results of 25 years of antiemetic research have been impressive, showing numerically large improvement with little in the way of adverse events.

 Unanswered Questions

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.[7] 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.[8]

Trials of metopimazine demonstrate that this drug has antiemetic activity,[9] 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.[10] 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.



4. Do cannabinoids have a role in this setting?

Cannabinoids are both old and "new" drugs. They were tested as antiemetics in the 1970s and largely abandoned because of toxicity (dysphoria, sedation) and the superior efficacy of high-dose metoclopramide. There have been no published studies of cannabinoids as add-on antiemetics in humans, although an animal model was encouraging. Cannabinoids remain an option as an add-on, but the evidence is anecdotal. The adverse effects of this drug class plus the stigma associated with the use of "marijuana-like" drugs greatly limit their use.

5. How can we reduce nausea?

Is nausea important? The answer is an unequivocal "yes." Nausea was listed as the most troublesome side effect of chemotherapy in a recent survey.[11]

Nausea and vomiting are conventionally thought of as being inextricably linked, but data from clinical trials suggest otherwise. Although the 5-HT3 receptor antagonists have substantially reduced the frequency of emesis, there is little evidence that the frequency of nausea has changed. A study of women receiving an anthracycline plus cyclophosphamide failed to show a reduction in nausea frequency or severity despite an impressive 17% reduction in emesis.[4] Interestingly, when the aprepitant data in the high-dose cisplatin studies were reanalyzed for a gender effect, aprepitant was at least as effective in women as in men, in terms of reducing the frequency of nausea due to cisplatin.[12] Thus, under certain conditions NK-1 receptor antagonists can reduce nausea, and this effect is not limited to males.

Solving the problem of chemotherapy-induced nausea will not be easy, since animal models do not exist.

Conclusions

Considerable advances have been made in the control of emesis, using a corticosteroid plus a 5-HT3 receptor antagonist with or without aprepitant. Guidelines agree on the two highest-risk groups for which aprepitant should be part of standard therapy (those receiving high-dose cisplatin and women receiving an anthracycline plus cyclophosphamide), but the role of this drug in antiemetic prophylaxis for other commonly administered agents is unclear. Although vomiting is still a problem for some patients, the biggest challenge for the future will be the prevention of nausea.

  -David Warr, MD, FRCPC

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References:

1. Jantunen IT, Kataja VV, Muhonen TT: An overview of randomised studies comparing 5-HT3 receptor antagonists to conventional anti-emetics in the prophylaxis of acute chemotherapy-induced vomiting. Eur J Cancer 33:66-74, 1997.

2. Ioannidis JP, Hesketh PJ, Lau J: Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: A meta-analysis of randomized evidence. J Clin Oncol 18:3409-3422, 2000.

3. Warr DG, Grunberg SM, Gralla RJ, et al: The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: Pooled data from 2 randomised, double-blind, placebo controlled trials. Eur J Cancer 41:1278-1285, 2005.

4. Warr DG, Hesketh PJ, Gralla RJ, et al: Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23:2822-2830, 2005.

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7. Kaiser R, Tremblay PB, Sezer O, et al: Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists. Pharmacogenetics 14:271-278, 2004.

8. Gralla RJ, Itri LM, Pisko SE, et al: Antiemetic efficacy of high-dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med 305:905-909, 1981.

9. Herrstedt J, Sigsgaard TC, Nielsen HA, et al: Randomized, double-blind trial comparing the antiemetic effect of tropisetron plus metopimazine with tropisetron plus placebo in patients receiving multiple cycles of multiple-day cisplatin-based chemotherapy. Support Care Cancer 15:417-426, 2007.

10. Horacek J, Bubenikova-Valesova V, et al: Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20:389-409, 2006.

11. Boer-Dennert M, de Wit R, Schmitz PI, et al: Patient perceptions of the side-effects of chemotherapy: The influence of 5HT3 antagonists. Br J Cancer 76:1055-1061, 1997.

12. Hesketh PJ, Grunberg SM, Herrstedt J, et al: Combined data from two phase III trials of the NK(1) antagonist aprepitant plus a 5HT(3) antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: Effect of gender on treatment response. Support Care Cancer 14:354-360, 2006.