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Originally published as JCO Early Release 10.1200/JCO.2003.10.128 on October 14 2003 © 2003 American Society for Clinical Oncology Addition of the Oral NK1 Antagonist Aprepitant to Standard Antiemetics Provides Protection Against Nausea and Vomiting During Multiple Cycles of Cisplatin-Based Chemotherapy
From the Rotterdam Cancer Institute, Rotterdam, The Netherlands; Copenhagen University Hospital, Herlev, Denmark; The Medical Oncology Centre of Rosebank, Johannesburg, S Africa; and Merck Research Laboratories, West Point, PA. Address reprint requests to Ronald De Wit, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute/Erasmus University Medical Center, P.O. Box 5201, 3008 Rotterdam, The Netherlands; e-mail: r.dewit{at}erasmusmc.nl.
Purpose: This analysis evaluated whether the antiemetic efficacy of the NK1 receptor antagonist aprepitant (EMENDTM, Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy.
Patients and Methods: Patients receiving cisplatin Results: In the first cycle, 64% of patients in the aprepitant group and 49% in the standard therapy group had a complete response. Thereafter, complete response rates for the aprepitant group were still 59% by cycle 6, but decreased to 34% by cycle 6 for the standard therapy group. Reasons for discontinuation were similar across treatment groups. Conclusion: Compared with patients who received standard therapy, those who received only the aprepitant regimen had better and more sustained protection against chemotherapy-induced nausea and vomiting over multiple cycles.
NAUSEA AND vomiting remain among the most distressing effects of treatment with chemotherapy.1,2 The use of a selective 5-HT3 receptor antagonist (RA) plus a corticosteroid such as dexamethasone prevents acute (day 1) emesis in 70% to 80% of patients in the first cycle of chemotherapy.3,4 Despite having reasonable protection from acute emesis, however, 25% to 40% of patients still experience vomiting and/or significant nausea in the delayed phase (days 2 to 5) of their first cycle of high-dose cisplatin.4,5 Few studies have assessed the efficacy of any preventive therapy for chemotherapy-induced nausea and vomiting (CINV) over multiple cycles of chemotherapy. The published studies that have evaluated efficacy in multiple cycles have produced discordant results, which may be as a result of the method of data analyses.6 The most accurate picture of clinical efficacy is obtained with a Markov method for transitional probabilities, which allows for inclusion of patients who had partial responses in prior cycles but who regained complete response in a subsequent cycle. This method includes all protection failures in the sum of failures during subsequent cycles, and incorporates censoring of the data due to non–cause-specific withdrawals. With this approach, it appears that the efficacy of current standard therapy with a 5-HT3 RA plus a corticosteroid is not well maintained over multiple cycles in patients receiving cisplatin-based or non–cisplatin-based chemotherapy.6–8 It has been shown that addition of the neurokinin-1 (NK1) RA aprepitant (EMENDTM) to a standard regimen of a 5-HT3 RA and dexamethasone provided superior protection in both the acute and delayed phases compared with standard therapy alone.9,10 The analysis described herein, performed using data from the multiple cycles extension of a study in which aprepitant plus a standard regimen conferred improved antiemetic control in cycle 1, evaluated whether this improved efficacy could be maintained in subsequent cycles.
All patients gave written informed consent to participate in this multicenter, randomized, double-blind, parallel-group, placebo-controlled trial, which was conducted in accordance with applicable country or local ethical requirements. Fifty centers in North America (including Mexico), South America, Europe, Africa, and Australia participated in the study (21 sites in the United States and 29 sites outside the United States).
Patient Population
Treatments During the study, new pharmacokinetic data in healthy subjects became available that showed that the plasma levels of aprepitant attained by the 375/250-mg regimen were higher than expected, and higher than required for attainment of 90% occupancy of central NK1 receptors. New data also suggested a pharmacokinetic interaction in which aprepitant increased dexamethasone levels by approximately two-fold (data on file). The 375/250-mg dose was therefore discontinued and, because only a small number of patients (n = 34) received that dose, the primary efficacy analysis focused on the aprepitant 125/80-mg group (n = 80) versus standard therapy (n = 84).
Highly emetogenic chemotherapeutic agents other than cisplatin were permitted only on day 1 of each cycle of cisplatin. Aside from the study drug, additional antiemetics including benzodiazepines, 5-HT3 RAs, phenothiazines, butyrophenones, benzamides, domperidone, or cannabinoids were not permitted within 72 hours of day 1 of cycle 1, except as rescue therapy for established nausea or emesis after cisplatin. Corticosteroid therapy equivalent to
One hour before receiving cisplatin, patients received the allocated aprepitant dose or placebo. Thirty minutes before cisplatin, all patients received intavenous ondansetron and oral dexamethasone. Cisplatin On days 2 to 5 of each cycle, patients took study medications at home every morning between 8:00 and 10:00. In addition, all patients received oral dexamethasone 8 mg. After each cycle of cisplatin-based chemotherapy, all patients returned to the clinic for a post-treatment visit between days 6 and 8, and for a follow-up safety visit between days 19 and 29, at which time a physical examination and laboratory tests were performed.
Assessments On days 2 to 6 of cycle 1, daily telephone contact was made by study site personnel to confirm that patients were taking study medications appropriately and maintaining accurate records. For each cycle, the diary was reviewed with the patient at the day 6 to 8 visit. Tolerability was monitored by physical examinations including vital signs and weight measurement, laboratory studies, and ECGs, as well as by adverse events. The investigator determined whether any adverse events were possibly, probably, or definitely related to the study drug.
Statistical Analysis The primary end point was complete response, defined as no emesis and no rescue therapy, over days 1 to 5 postcisplatin. A modified intention-to-treat approach was used for the efficacy analysis. To be considered assessable, a patient had to have received at least one dose of the study drug and cisplatin and had to have recorded at least one post-treatment efficacy assessment. The primary efficacy analyses were performed using a three-outcome model of transitional probabilities.6,7 Patients were considered to have experienced one of the following three possible outcomes: complete, partial, or failed response. For the primary end point of complete response, the following definitions were used: complete response = no emesis and no use of rescue therapy; partial response = zero to two emetic episodes and no use of rescue therapy; and failed response = more than two emetic episodes and/or use of rescue therapy. Of primary interest was the probability of achieving a complete response in a given cycle. If a patient had a complete or partial response in a cycle and continued in the study, the patient could then have had a complete response, a partial response, or a failure in the next cycle. Patients who failed a cycle were considered failed for all subsequent cycles. Although these patients were not automatically discontinued from the study, their efficacy data were censored in the probability computations for subsequent cycles. Likewise, patients who withdrew or discontinued for reasons other than antiemetic protection failure were not included in the efficacy analysis for subsequent cycles. Therefore, the probability computations for each cycle were based on an assessable population consisting of those patients who had a complete response in the cycle being assessed, and who also had either a complete or partial response in all previous cycle(s). This approach allows for fluctuation in a patient’s level of response from cycle to cycle without actual treatment failure. In cycle 1, data were obtained from patients who were randomly allocated to treatment groups; allocation was stratified by sex and use of concomitant emetogenic chemotherapy. The treatment comparison in cycle 1 was performed using logistic regression with factors for treatment, sex, use of concomitant emetogenic chemotherapy, and region. For cycles 2 to 6, treatment comparisons for each cycle were performed using the bootstrap method for the calculation of standard error; normal theory was applied to obtain confidence intervals and P values, and nominal P values were reported. Safety data were assessed using tabulations of adverse events for all patients who participated in the study through at least the pre- cycle 2 clinic visit. Tolerability data from cycle 1 were examined as part of a separate, larger analysis of patients taking aprepitant in their first cycle of cisplatin.12 The tolerability profile of interest in the present study was that of repeated dosing with aprepitant (ie, over at least two cycles of chemotherapy). All adverse event data collected over cycles 2 to 6 were tabulated.
Accounting for Patients A total of 202 patients were enrolled onto the study. Figure 1  shows the disposition of patients throughout the study. Baseline characteristics of patients in cycle 1 were similar across treatment groups (Table 1). The mean dose of cisplatin, use of additional chemotherapeutic agents including highly emetogenic chemotherapy, alcohol intake and use of concomitant medications (data not shown) were also similar across treatment groups, as were the primary cancer diagnoses (Table 1) and secondary diagnoses (data not shown). Of the 202 patients who participated in cycle 1, 57 patients did not continue in the study beyond cycle 1, for reasons including completion of the study (35 patients), occurrence of a clinical or laboratory adverse event (10 patients), withdrawal of consent (five patients), protocol deviation (three patients), or other reasons (four patients).
A total of 145 patients completed a prestudy visit for cycle 2; of these, 141 received the study drug in cycle 2. In the aprepitant 125/80-mg and standard therapy groups, similar numbers of patients continued through multiple cycles, with more women than men continuing in the study. As the cycles progressed, the mean cisplatin dose dropped across the treatment groups, although the minimum dose of 70 mg/m2 required by the protocol was maintained through all cycles. The use of rescue therapy (for established nausea or emesis after cisplatin administration) was similar across the treatment groups throughout multiple cycles, as were reasons for discontinuation (Fig 2 ). The most common reason for discontinuation was the completion of chemotherapy.
Efficacy For the primary end point of complete response, Table 2 and Figure 2 depict the probabilities (referred to as "rates") estimated for each cycle using the transitional probability approach. In the aprepitant group, all patients with complete response in cycles 5 and 6 had complete response consistently throughout all cycles (ie, none of these patients had had a partial response). In the mathematical calculation of transitional probabilities, this result would have given a term of "0/0," or infinity, which is not meaningful. The term was therefore considered to be 0, representing "no patients," for the purposes of calculating probabilities.
Assessment of the overall complete response rates by treatment group over the six cycles showed that the aprepitant 125/80-mg group had higher and better sustained rates than did the standard therapy group. Inspection of the data showed that within the aprepitant group, there was essentially no change in response rate between cycle 1 (64%) and cycle 6 (59%). By contrast, within the standard therapy group, the complete response rate declined 15 percentage points between cycle 1 (49%) and cycle 6 (34%; between-treatment comparisons of percentage-point changes not statistically analyzed).
Statistical comparison of the two treatment groups performed for cycle 1 showed that the 15-percentage point difference in complete response rate between the two treatment groups (64% in the aprepitant group and 49% in the standard therapy group) was significant (P < .05, calculated using logistic regression model). Likewise for cycles 5 and 6, the 25-percentage point superiority of the aprepitant group was also significant (59% in cycles 5 and 6 for the aprepitant group, and 34% in cycles 5 and 6 for the standard therapy group; P < .05, calculated using the bootstrap method). In addition, the percentage of failures was calculated for each group as the number of failures over the six cycles, divided by the number of patients in cycle 1. Failures (calculated as the number of failures over the six cycles divided by the number of patients in cycle 1) were more prominent in the standard therapy group (51.2%) than in the aprepitant 125/80-mg group (36.3%). No hypothesis was tested regarding this difference (Table 2 Although no formal statistical comparisons were performed for the aprepitant 375/250-mg group and the data should be interpreted with caution due to the small number of patients who received this dose, the rates of complete response (70% in cycle 1 and 65% in cycle 6) were similar to those with 125/80 mg and consistently higher than rates for standard therapy.
Tolerability
Adverse events were defined as serious according to a standard regulatory definition, which included the following stipulations: the adverse event either resulted in death, was life-threatening, resulted in persistent or significant disability, resulted in or prolonged existing inpatient hospitalization, or was a congenital anomaly. There were 29 patients who had serious clinical adverse events over cycles 2 to 6 (two in the aprepitant 375/250-mg group, 16 in the aprepitant 125/80-mg group, and nine in the standard therapy group), and six of these patients died. As noted, none of the serious adverse events were believed to be drug-related by investigators. Of the six deaths, three were in the aprepitant 125/80-mg group and three were in the standard therapy group. In the aprepitant 125/80-mg group, the causes of death were progression of cancer and respiratory insufficiency (one patient), progression of cancer (one patient), and hemoptysis (one patient), and for the standard therapy group the causes of death were cardiac arrest (two patients) and metastasis (one patient). In all cases, the patient had completed the 5-day regimen of study therapy. Among the reported serious adverse events over cycles 2 to 6, there were no cases of renal failure, renal insufficiency, or increase in serum creatinine or blood urea. Fifteen infection-related serious adverse events occurred in cycles 2 to 6 (11 patients in the aprepitant 125/80-mg group and one patient in the standard therapy group). Of patients who had serious febrile neutropenia in cycles 2 to 6, none were in the aprepitant 375/250-mg group compared with 9.7% (six patients) in the aprepitant 125/80-mg group and 1.7% (one patient) in the standard therapy group. In addition, one patient in the aprepitant 125/80-mg group had a nonserious adverse event of febrile neutropenia in cycles 2 to 6.
The most common clinical adverse events ( The incidence of laboratory adverse events in cycles 2 to 6 was comparable in the aprepitant 375/250-mg group (21.7%), aprepitant 125/80-mg group (25.8%), and the standard therapy group (26.7%). Two patients, both in the aprepitant 125/80-mg group, discontinued due to laboratory adverse experiences, and only one serious laboratory adverse experience (serum creatinine increase) was reported (one patient in the aprepitant 125/80-mg group). There were no deaths due to laboratory adverse experiences in any treatment group. The incidence of hematologic toxicity (anemia, leukopenia, neutropenia, and thrombocytopenia) across treatment groups was comparable as assessed by protocol-specified tests done at the day 6 to 8 and day 19 to 29 visits in all cycles. The pattern of National Cancer Institute toxicity grade-3 or grade-4 elevation in liver function tests (ALT or AST) was also similar across groups.
CINV tends to become more severe over multiple cycles,6,7,8 and the level of antiemetic protection achieved in one cycle of chemotherapy has been noted to affect the severity of symptoms during, or even in anticipation of, subsequent cycles. Up to 30% of patients experience anticipatory symptoms by their fourth cycle of chemotherapy, and this type of CINV tends to be refractory to current antiemetic therapy.13 Because most patients receive more than one cycle of chemotherapy, a need clearly exists for antiemetic protection that is both robust and sustainable. The relatively few formal assessments of current therapy administered over multiple cycles of chemotherapy have yielded inconsistent results, which are difficult to interpret comparatively because of the use of different statistical methods of data analysis. The findings of recent studies by de Wit et al,6,7 in which a 3-state model of assessment using transitional probabilities was employed, showed that over multiple cycles, adequate efficacy was not maintained by a 5-HT3 RA or the combination of a 5-HT3 RA plus dexamethasone.8 We adopted a similar analytic approach in the present study of the NK1 RA aprepitant for the prevention of CINV over multiple cycles of chemotherapy. In clinical studies, aprepitant has demonstrated good efficacy against single-cycle CINV, with notable superiority to current therapy in the control of delayed symptoms. Because the best protection against CINV to date has been achieved with a combination of aprepitant, a 5-HT3 RA, and dexamethasone,10 we expected that this superior protection in an initial cycle would also provide improved control over subsequent cycles. Baseline characteristics of patients in the study were similar across treatment groups, and a similar number of patients in the aprepitant 125/80-mg group and the standard therapy group continued in the study beyond cycle 1. Reasons for discontinuation and rates of discontinuation were similar, and the mean dose of cisplatin also remained comparable across groups. There were few patients in the aprepitant 375/250-mg group due to the early discontinuation of that dose regimen for pharmacokinetic reasons; this group was consequently excluded from the primary efficacy analyses. As analyzed by the 3-state model using transitional probabilities, aprepitant 125/80-mg plus standard therapy provided sustained antiemetic control over multiple cycles in terms of complete response (no emesis and no use of rescue therapy), with essentially no change in response rate from cycle 1 to cycle 6, whereas protection afforded by standard therapy alone diminished over subsequent cycles. Rates of complete response for aprepitant 125/80-mg were consistently at least 34% better than those for standard therapy. The aprepitant regimen was significantly superior to standard therapy in cycles 5 and 6 as well as in cycle 1, demonstrating that the addition of aprepitant provided a benefit that was well sustained over multiple cycles of chemotherapy. The adverse event profile observed during repeated dosing with aprepitant in this study was typical of cancer patients receiving high-dose, cisplatin-based chemotherapy. Patients were evaluated who participated in at least a precycle 2 visit, nearly all of whom received the study drug for at least two cycles, and the safety assessments were made on data obtained for cycles 2 to 6. Data obtained from cycle 1 of the study were analyzed in a larger analysis of patients taking aprepitant for a single cycle.13 The incidence of clinical and laboratory adverse events in patients taking aprepitant over multiple cycles was generally similar across treatment groups and in the larger analysis of cycle 1 data, the overall safety profile was observed to be similar to that seen in the present study.13 Although no patient treated during multiple cycles had serious adverse events interpreted by the investigator as related to the study drug, a higher incidence of serious adverse events was observed in the aprepitant 125/80-mg group versus standard therapy. The difference is ascribable to the greater numbers of patients in the aprepitant group who had febrile neutropenia and various infection-related adverse events, and removal of these events from the comparisons renders the treatment groups similar in terms of the incidence of serious adverse events. A comprehensive discussion of this finding is presented in the larger analysis of patients taking aprepitant in a single cycle of chemotherapy; it is hypothesized that the higher incidence of infection-related serious adverse events may have been a result of the increased exposure to dexamethasone associated with aprepitant, a consequence of the pharmacokinetic interaction.13 This hypothesis was examined in two recently conducted phase III trials that used a modified dexamethasone regimen in patients taking aprepitant to produce more closely matched dexamethasone levels in patients who received aprepitant versus those who received only standard therapy. As anticipated, the safety analyses in these studies showed no differential incidence of serious infection-related adverse events or of febrile neutropenia.14,15 A recent study of the differential patterns of efficacy of the NK1 RA aprepitant compared with a 5-HT3 RA strongly suggested the involvement of 2 different mechanisms mediating emesis in the hours and days following a cycle of cisplatin.16 In that study, emesis in the early acute phase (0 to 8 hours) appeared to be preferentially responsive to a 5-HT3 RA and therefore likely mediated by serotonin-based mechanisms, whereas beyond 8 to 12 hours postcisplatin, emesis was particularly responsive to the NK1 RA and was therefore more likely mediated by substance P acting at neurokinin-1 receptors. These observations provided a rationale for combining both drugs for improved control of acute and, more notably, delayed emesis after a single cycle of cisplatin-based chemotherapy. An important aspect of antiemetic efficacy over multiple cycles may hinge on the strong correlation which appears to exist between failure in the delayed phase of a cycle and a poor outcome in the acute phase of the next cycle.7 Within the aprepitant groups in the present study, rates of complete response did not vary by more than 6 percentage points across all six cycles, in contrast to the standard therapy group, in which complete response decreased by as much as 15 percentage points by cycle 6. Because the difference between the groups was the presence or absence of the NK1 RA with its known efficacy against delayed emesis in particular, it may be possible that groups receiving aprepitant experienced better delayed-phase control within cycles, which may have then functioned as a critical "positive feedback" mechanism in maintaining good protection from one cycle to the next. In summary, the addition of aprepitant to a standard therapy regimen consisting of a 5-HT3 RA plus dexamethasone enhanced not only single-cycle antiemetic protection, but also maintained the enhanced protection over multiple cycles to an extent superior to that of standard therapy alone. The benefit of the combination of aprepitant plus standard therapy was clinically apparent as an almost two-fold increase (from 34% to 59%) in a patient’s chance of remaining free of emesis and of the need for rescue medication (which directly suggests freedom from significant nausea) throughout six cycles of chemotherapy. Although further study is needed of the impact of aprepitant on anticipatory emesis, the apparent ability of aprepitant to stabilize a higher level of antiemetic protection over multiple cycles of cisplatin would be expected to have a mitigating effect on emesis that occurs in response to a prior experience of CINV.
The following authors or their immediate family members have indicated a financial interest. No conflict of interest exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): A.D. Carides, Merck; C. Schmidt, Merck; J.K. Evans, Merck; K.J. Horgan, Merck. Acted as a consultant within the last two years: R. de Wit, Merck; J Herrstedt, Merck. Served as an officer or member of the board of a company: K.J. Horgan, Merck. Received more than $2,000 a year from a company for either of the last two years: R. de Wit, Merck; M. Elmer, Merck; C. Schmidt, Merck; J.K. Evans, Merck; K.J. Horgan, Merck.
Funded by Merck Research Laboratories, the manufacturer of aprepitant.
1. 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 7:189–195, 1996 2. de Boer-Dennert M, de Wit R, Schmitz PIM, et al: Patient perceptions of the side-effects of chemotherapy: the influence of 5-HT3 antagonists. Br J Cancer 76:1055–1061, 1997[Medline] 3. Hesketh PJ: Treatment of chemotherapy-induced emesis in the 1990s: impact of the 5-HT3 receptor antagonists. Support Care Cancer 2:286–292, 1994[CrossRef][Medline]
4. Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 17:2971–2994, 1999 5. Tavorath R. Hesketh PJ: Drug treatment of chemotherapy-induced delayed emesis. Drugs 52:639–648, 1996[Medline]
6. de Wit R, Schmitz PIM, Verweij J, et al: Analysis of cumulative probabilities shows that the efficacy of 5HT3 antagonist prophylaxis is not maintained. J Clin Oncol 14:644–651, 1996 7. de Wit R, van den Berg H, Burghouts J, et al: Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles. Br J Cancer 77:1487–1491, 1998[Medline]
8. Sigsgaard T, Herrstedt J, Handberg J, et al: Ondansetron plus metopimazine compared with ondansetron plus metopimazine plus prednisolone as antiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy. J Clin Oncol 19:2091–2097, 2001
9. Campos D, Pereira JR, Reinhardt RR, et al: Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 19:1759–1767, 2001
10. Navari R, Reinhardt R, Gralla RJ, et al: Reduction of cisplatin-induced emesis by a selective neurokinin-1 receptor antagonist. N Engl J Med 340:190–195, 1999
11. Hesketh PJ, Kris MG, Grunberg SM, et al: Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 15:103–109, 1997 12. Chawla SP, Gralla RJ, Hesketh PJ, et al: Establishing the dose of the oral NK1 antagonist aprepitant for chemotherapy-induced nausea and vomiting. Cancer 97:2290–2300, 2003[CrossRef][Medline] 13. Morrow GR, Roscoe JA, Kirshner JJ, et al: Anticipatory nausea and vomiting in the era of 5HT3 antiemetics. Support Care Cancer 6:244–247, 1998[CrossRef][Medline] 14. Poli-Bigelli S, Rodrigues-Pereira J, Carides A, et al: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy induced nausea and vomiting. Results from a randomized, double-blind, placebo controlled trial in Latin America. Cancer 97: 3090–3098, 2003[CrossRef][Medline]
15. Hesketh PJ, Grunberg SM, Gralla RJ, et al: The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—The Aprepitant Protocol 052 Study Group. J Clin Oncol: 21:4112–4119, 2003 16. Hesketh PJ, Van Belle S, Aapro M, et al: Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39: 1074–1080, 2003[CrossRef][Medline] Submitted October 23, 2002; accepted July 24, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 mg/m2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5. The primary end point was complete response (no emesis and no rescue therapy) over 5 days following cisplatin in up to six cycles. A cumulative probability analysis using a model for transitional probabilities was used to analyze the data. The aprepitant 375/250-mg regimen was discontinued early in light of new pharmacokinetic data. 
10 mg of prednisone was permitted provided it was not initiated within 72 hours of day 1 of cycle 1. 
