Before the 1980s, chemotherapy-induced vomiting occurred in a preponderance of patients who received cisplatin or doxorubicin. In the 1990s, an antiemetic combination of a corticosteroid and a 5-HT₃ receptor antagonist became common practice for many cyto-toxic regimens. By the early part of that decade, that antiemetic combination had had a noticeable impact on admissions to hospital for control of emesis, leading to cost savings 9. But despite that progress, substantial problems with nausea and vomiting remained.

In two large randomized trials, 50% of patients receiving high-dose cisplatin still experienced vomiting and 58% experienced nausea in the face of standard antiemetic therapy 1. Although traditionally regarded as “moderately emetogenic,” anthracycline and cyclophosphamide chemotherapy for breast cancer evoked vomiting in 41% of patients and nausea in 67% following ondansetron and dexamethasone 10. Those outcomes were vastly better than the outcomes seen in the 1980s, but considerable room for improvement remained.

Several large comparative studies showed no difference in efficacy between ondansetron, granisetron, and dolasetron 11,12. The prevailing belief was that all 5-HT₃ receptor antagonists were equivalent in efficacy and in side effects when delivered in the recommended doses. That paradigm was challenged by palonosetron, an intravenous 5-HT₃ receptor antagonist with a sufficiently long half life that a single administration was sufficient 13.

In patients who received moderately emetogenic chemotherapy, two large randomized trials showed superiority for palonosetron over ondansetron 14 and dolasetron 15. In contrast, palonosetron appeared to be equivalent to ondansetron in patients who received high-dose cisplatin 16. Despite those results, the American Society of Clinical Oncology (asco) guide- lines do not recognize palonosetron as the 5-HT₃ receptor antagonist of choice, because the therapies used in the study comparator arms were not regarded as best standard therapy 17. The true role for palonosetron will be confidently established only by randomized trials in which the standard therapy conforms to recommended practice.

Also in the 1990s, a new of class of antiemetics was discovered: the neurokinin 1 (NK₁) receptor antagonists 18 . The NK₁ receptor has substance P as its natural ligand and is present both peripherally and centrally. Aprepitant is the only example of the NK₁ antagonist class that has proceeded through phase iii testing.

Aprepitant is commercially available in many countries around the world. Its efficacy has been evaluated in four phase iii double-blind randomized studies—three with high-dose cisplatin 19–21 and one with chemotherapy containing an anthracycline plus cyclophosphamide for breast cancer 10. The standard therapy arms contained ondansetron and dexamethasone; in the experimental arm, aprepitant in the currently approved dose and schedule was added to ondansetron and dexamethasone. All trials reported primary endpoints that were statistically significantly superior in the group receiving aprepitant (Table IV). A complete response was defined as an absence of retching or vomiting and no use of an “as-needed” antiemetic.

The cisplatin studies showed a 14%–20% absolute difference in complete response when aprepitant was added; in moderately emetogenic chemotherapy, the difference was only 9%. The apparently lesser improvement with the addition of an NK₁ receptor antagonist to chemotherapy containing anthracycline plus cyclophosphamide was further explored by looking at nausea separately from vomiting or retching. Aprepitant had no detectable effect on nausea attributable to moderately emetogenic chemotherapy 10, but a statistically significant improvement was observed in the pivotal cisplatin studies 1. In contrast, for vomiting or retching alone, the superiority in the aprepitant groups was similar across the phase iii studies: a 17% difference in the moderately emetogenic trial and a 14.3%-to-22.7% difference in the cisplatin trials (Table IV). Thus, the improved control of vomiting provided by aprepitant was approximately the same whether the chemotherapy was high-dose cisplatin or cyclophosphamide and doxorubicin; however, the beneficial effect of aprepitant on nausea seemed to be limited to settings involving high-dose cisplatin. The reason for the difference is not known.

Because aprepitant is a moderate inhibitor of the cytochrome P450 enzyme (CYP3A4), concern initially arose about whether aprepitant might affect the clearance of taxanes and vinca alkaloids that are metabolized by that enzyme. Adverse effects in the aprepitant-containing arms of the phase iii trials appeared very similar to those seen in standard therapy, with no trends across the studies even though patients commonly received concomitant taxanes, vinorelbine, or etoposide 1,10. Subsequent pharmacokinetic studies that showed no effect of aprepitant on the clearance of docetaxel 22 or vinorelbine 23 were consistent with the foregoing observations.

Although no interaction with intravenous medications has thus far been demonstrated, aprepitant may have clinically relevant interactions with oral agents that have an extensive first-pass metabolism connected with CYP3A4 in the bowel wall. For example, dexamethasone is metabolized by CYP3A4, and co-administration with aprepitant results in a doubling of the area under the curve of the corticosteroid^24. For that reason, the phase iii clinical trials were designed to deliver approximately one half the dose of dexamethasone in the group that received aprepitant. Aprepitant would also be expected to temporarily increase the blood levels of other oral agents metabolized by CYP3A4—as do ketoconazole, erythromycin, diltiazem, and a number of other commonly prescribed medications. Through induction of enzymes, aprepitant reduces warfarin levels by approximately one third 25, and the aprepitant product monograph indicates that aprepitant may reduce the efficacy of the birth control pill. Because aprepitant itself is metabolized by CYP3A4, strong inducers of that enzyme such as rifampin and phenytoin may lower blood levels of the drug sufficiently to make it ineffective.

Aprepitant is an oral medication. It supplied as a 3-day pack: 125 mg on day 1, and 80 mg on each of days 2 and 3. Approval is being sought for a single intravenous dose of a prodrug that yields an area under the curve similar to that seen with oral aprepitant.

Standard antiemetic therapy recommended by asco 17 and the Multinational Association for Supportive Care in Cancer 26 now includes aprepitant for chemotherapy with cisplatin and with anthracycline plus cyclophosphamide. Still, several questions remain about aprepitant use:

• What should be done for patients taking other emetogenic chemotherapy such as carboplatin or ifosfamide?
• What should the aprepitant dosing schedule be for multiple-day cisplatin?
• Does aprepitant have a role as a second-line antiemetic?

Aprepitant is an important step forward, but some patients still vomit or experience substantial nausea despite its use. In addition, aprepitant is not available in some countries, and like the 5-HT₃ receptor antagonists, it is relatively expensive and may therefore not be an option for some patients. Other agents that might be added include a dopamine receptor antagonist (for example, prochlorperazine), a cannabinoid (nabilone or dronabinol), and the atypical antipsychotic olanzapine. Prochlorperazine appears to have very modest effects on chemotherapy-induced nausea and vomiting 27. Cannabinoids have some anecdotal support, but the data from clinical trials antedate the introduction of 5-HT₃ receptor antagonists, and in recommended doses, significant problems with sedation and dysphoria arise. Olanzapine blocks multiple receptors, including dopamine receptors 28. Anecdotal accounts and phase ii studies suggest an important antiemetic effect 29,30, but phase iii data are not yet available.

Tables V and VI outline a reasonable approach to antiemetic therapy that is consistent with the available evidence.