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PRIORITY PRESS - 45th Annual Meeting of the American Society of Clinical Oncology

Orlando, Florida / May 29-June 2, 2009

The evidence that newer options substantially increase the opportunity to reduce chemotherapy-related nausea and vomiting (CINV) appears to be outpacing changes in practice that are needed to put this information to practical use. Most patients receive some form of prophylaxis for moderately or highly emetogenic chemotherapy regimens, but surveys suggest that clinicians are not sufficiently aggressive in applying new combinations that are needed in higher-risk patients. The addition of neurokinin-1 (NK₁) antagonists for a combination approach is considered to be the cornerstone of more comprehensive risk control and applicable to individuals taking only moderately emetogenic regimens.

Adjusting Therapies to Relative Risk Essential

“Current anti-emetic guidelines recommended different treatments depending on the type of chemotherapy even for moderately emetogenic regimens,” reported Dr. Hans J. Schmoll, Martin Luther University Halle-Wittenberg, Germany. He indicated that the standard selective serotonin (5-HT₃) receptor antagonists are being augmented, not replaced, with the newer NK₁ antagonists, which have been associated with a more complete control of both nausea and vomiting when added to 5-HT₃ receptor antagonists in multicentre and controlled trials.

The 2006 ASCO guidelines already identify the combination of a 5-HT₃ receptor antagonist, the NK1 antagonist aprepitant and dexamethasone as the regimen of choice for chemotherapy of high emetogenic risk, but Dr. Schmoll indicated new data extend the evidence to other groups. He reported that numerous studies have been conducted that demonstrate benefit in a broader population at risk, including a new multicentre trial conducted in patients taking moderately emetogenic chemotherapies for which he served as the first author.

In this study, 848 patients with a histologically confirmed malignancy and a predicted life expectancy of at least four months were enrolled and randomized. The study compared the relative contribution of the addition of aprepitant to a three-drug regimen containing the 5-HT₃ receptor antagonist ondansetron and the corticosteroid dexamethasone. On day 1, patients in the NK₁ antagonist group received 125 mg one hour before chemotherapy plus ondansetron 8 mg 30 to 60 minutes before and then eight hours after chemotherapy, and dexamethasone 12 mg 30 minutes before chemotherapy. On days 2 and 3, patients received aprepitant 80 mg, placebo ondansetron and no dexamethasone. In the control arm, patients received placebo aprepitant on days 1, 2 and 3. They received the same two doses of ondansetron as the study arm on day 1 followed by ondansetron 8 mg b.i.d. on days 2 and 3. Dexamethasone was given only on day 1 in a dose of 20 mg 30 minutes before chemotherapy.

One or more of a wide range of emetogenic chemotherapies were permitted in the randomized patients including oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin and doxorubicin. Patients had to be taking <1500 mg/m² cyclophosphamide but >1 g/m² of cytarabine. Systemic corticosteroids were an exclusion criterion as were treatments such as cisplatin that would elevate emetogenic risk above the moderate level sought for the study population. There were also a broad range of tumour types represented in the study population, including breast, lung, gastrointestinal and gynecologic. The primary end point was no vomiting during the five days following initiation of chemotherapy.

The relative advantage of adding aprepitant was highly significant and consistent across regimens and cancer types. On the primary end point over the five days after chemotherapy, 76.2% of patients in the control group had an episode of vomiting vs. 61.1% (P<0.001) in the arm receiving the NK₁ antagonist. For the more rigorous secondary end point of no emetic episodes and no rescue therapy over the same five days, the rates were 56.3% vs. 68.7% (P<0.001), respectively. The rate of adverse events and types of adverse events did not differ significantly in the two study arms.

“The addition of aprepitant to an anti-emetic regimen of ondansetron and dexamethasone results in significantly improved prevention of chemotherapy-induced vomiting in all phases for patients with diverse malignancies who received a broad range of moderately emetogenic regimens,” Dr. Schmoll told delegates. He indicated that the 75% incidence of vomiting in the control arm underscores the need for longer and more aggressive prophylaxis even for regimens considered to be only moderately emetogenic.

Anti-emesis Mechanism of Action: Timing is Everything

The strategy of combining anti-emetic therapies is based on the enhanced control anticipated both from independent mechanisms of action and from the differences in the timing of peak pharmacologic effect. In highly emetogenic chemotherapy regimens such as those containing cisplatin, aprepitant has been a guideline-supported addition to vomiting control because it is more effective than 5-HT₃ receptor inhibitors in controlling the second peak of the biphasic pattern of emesis associated with these regimens. In moderately emetogenic chemotherapy such as that imposed by anthracycline chemotherapy, there is a monophasic peak in vomiting, but the NK₁ antagonist is active early and adds a second mechanism of control.

“Both 5-HT₃- and NK₁-sensitive mechanisms are important in the first 12 hours after moderately emetogenic chemotherapy,” explained Dr. Paul J. Hesketh, St. Elizabeth’s Medical Center, Boston, Massachusetts. Referring to a time-of-onset analysis he conducted using data from three studies of aprepitant for vomiting control in highly or moderately emetogenic chemotherapy, Dr. Hesketh reported statistically significant protection against the second emesis peak in patients taking cisplatin-based highly emetogenic chemotherapy and a statistically significant reduction in the first 12 hours of patients taking an anthracycline-based moderately emetogenic chemotherapy regimen for breast cancer.

In all three studies, in which a total of 856 patients were randomized and assessed for efficacy, the addition of aprepitant to ondansetron and dexamethasone was compared to ondansetron and dexamethasone alone. The post-hoc analysis evaluated the impact of aprepitant on emesis at different time intervals using a multivariate logistic regression analysis. “The NK₁ receptor antagonists have demonstrated activity in both the first 24 hours and, to an even greater extent, during the period beyond 24 hours, whereas the 5-HT₃ receptor antagonists have had a less consistent effect,” Dr. Hesketh noted. “Our results provide the basis for the observed benefits early after chemotherapy with aprepitant in moderately emetogenic regimens. Both types of agents work in controlling emesis even in a monophasic pattern of risk.”

Study Findings

These same effects were seen in a series of smaller recently completed studies. In one, from a team of investigators from the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 95 patients were evaluated after receiving either a highly emetogenic or moderately emetogenic regimen. An observational study, this analysis included a survey of 29 physicians and nurses for their predictions of the risk of vomiting. The survey found that clinicians underestimated the risk of nausea from moderately emetogenic regimens by up to 28%, but noted that aprepitant was associated with improved vomiting control in both highly emetogenic and moderately emetogenic regimens.

In a series of 17 patients evaluated in a collaborative study at Wake Forest University and University of North Carolina-Greensboro, the addition of aprepitant to a 5-HT₃ antagonist and dexamethasone permitted approximately 60% of patients to avoid nausea and vomiting, a substantial improvement over a comparison to historical controls. In a third study, conducted at the Mount Sinai Medical Center, New York City, 12 patients undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation were included. Again, the addition of aprepitant to the 5-HT₃ antagonist ondansetron plus metoclopramide decreased the frequency of chemotherapy-induced nausea vs. a control group that did not receive the NK₁ antagonist.

Summary

The introduction of a NK₁ antagonist has substantially increased the likelihood for control of CINV for moderate and highly emetogenic chemotherapy risk. In highly emetogenic chemotherapy, the advantage of aprepitant is attributed to improved control over the characteristic second peak of emesis. In moderately emetogenic chemotherapy, the advantage is conferred by a second mechanism of emesis suppression. The efficacy of more aggressive combination regimens is expected to affect the next set of clinical guidelines.