Supportive Care in Cancer

, 14:354

Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response

Authors

    • Caritas St. Elizabeth’s Medical Center
  • S. M. Grunberg
    • University of Vermont
  • J. Herrstedt
    • Copenhagen University Hospital Herlev
  • R. de Wit
    • Rotterdam Cancer Institute & University Hospital
  • R. J. Gralla
    • New York Lung Cancer Alliance
  • A. D. Carides
    • Merck Research Laboratories
  • A. Taylor
    • Merck Research Laboratories
  • J. K. Evans
    • Merck Research Laboratories
  • K. J. Horgan
    • Merck Research Laboratories
Original Article

DOI: 10.1007/s00520-005-0914-4

Cite this article as:
Hesketh, P.J., Grunberg, S.M., Herrstedt, J. et al. Support Care Cancer (2006) 14: 354. doi:10.1007/s00520-005-0914-4

Abstract

Goals of work

Prevention of chemotherapy-induced nausea and vomiting (CINV) with standard antiemetics has been more difficult to achieve in female patients. Data from two phase III trials of the NK1 antagonist aprepitant were assessed for potential effect of gender on treatment response.

Patients and methods

1,044 patients receiving cisplatin (≥70 mg/m2) were randomly assigned to control regimen [ondansetron (O) 32 mg i.v. and dexamethasone (D) 20 mg p.o. on day 1; D 8 mg twice daily on days 2–4] or aprepitant (A) regimen (A 125 mg p.o. plus O 32 mg and D 12 mg on day 1; A 80 mg and D 8 mg once daily on days 2–3; and D 8 mg on day 4). The primary endpoint was overall complete response (no emesis and no rescue therapy over days 1–5). Data were analyzed by a modified intent-to-treat approach. Between-treatment comparisons for each gender were made using logistic regression.

Main results

Women comprised 42 and 43% of the aprepitant and control groups, respectively. In the control group, 41% of women had overall complete response compared with 53% of men. In the aprepitant group, 66% of women had overall complete response compared with 69% of men.

Conclusion

The addition of aprepitant may negate the adverse prognostic effect of female gender on the prevention of CINV in patients receiving highly emetogenic chemotherapy.

Keywords

Nausea and vomitingAprepitantNK1 antagonistCancerSupportive care

Introduction

Although the efficacy of treatment regimens in preventing chemotherapy-induced nausea and vomiting (CINV) has improved significantly in recent years with the advent of the 5HT3 receptor antagonists [10], reports indicate that up to 50% of patients receiving highly emetogenic chemotherapy such as cisplatin still experience CINV [1, 10, 11, 25]. Moreover, certain characteristics of patients receiving emetogenic chemotherapy have been observed to be associated with greater risk of CINV; female gender has been well recognized as a significant risk factor, and CINV has been reported to be more difficult to prevent in women [7, 10, 11, 13, 18, 19, 24]. Significantly inferior antiemetic protection for women vs men has been reported in several large trials, including studies of 5HT3 receptor antagonists [13, 22]. Although the exact mechanism(s) underlying the increased risk for female patients remains to be established, there is clearly a need for better antiemetic protection in women receiving chemotherapy.

In two identically designed, randomized, double-blind trials, the addition of the NK1 receptor antagonist aprepitant (EMEND) to a control regimen (a 5HT3 antagonist plus a corticosteroid) in patients receiving high-dose cisplatin-based chemotherapy significantly improved antiemetic protection in both the acute (0–24 h postchemotherapy) and delayed (24–120 h postchemotherapy) phases of CINV [12, 17]. To assess the impact of aprepitant on CINV prevention among female patients, data from these two studies were pooled for treatment comparisons by gender.

Patients and methods

Design

All patients gave written informed consent to participate in these identically designed randomized, double-blind, parallel-group, placebo-controlled trials, both of which were conducted in accordance with applicable ethical requirements. Detailed descriptions of the design and primary efficacy and tolerability results of both studies are published elsewhere [12, 17].

Patients

Cisplatin-naive patients more than 18 years of age with a Karnofsky score ≥60 who were scheduled to receive their first cycle of chemotherapy including cisplatin ≥70 mg/m2 were enrolled. All patients had histologically confirmed solid tumors. Patients who met entry criteria were assigned to one of two treatment groups; randomization was stratified by gender and by concomitant emetogenic chemotherapy due to the known importance of these characteristics as risk factors. Patients in the control regimen group received 32 mg intravenous ondansetron and 20 mg oral dexamethasone on day 1, followed by 8 mg oral dexamethasone twice daily on days 2–4. Patients in the aprepitant group received 125 mg oral aprepitant plus 32 mg intravenous ondansetron and 12 mg oral dexamethasone on day 1, 80 mg oral aprepitant and 8 mg oral dexamethasone once daily on days 2 and 3, and 8 mg oral dexamethasone on day 4.

One hour before cisplatin, patients received either aprepitant or placebo. Thirty minutes before cisplatin, all patients received ondansetron and dexamethasone, and cisplatin was then infused over a period of ≤3 h. Patients receiving docetaxel or paclitaxel in addition to cisplatin were premedicated with two doses of dexamethasone (20 mg) before paclitaxel or docetaxel infusion. Additional chemotherapeutic agents of Hesketh emetogenic level ≥3 were permitted only on day 1; patients could not have received such agents within 6 days prior to day 1 or within 6 days following day 1. Patients also could not receive additional antiemetics within 2 days before day 1 or between days 1 and 6 of the study, unless such medications were given as rescue therapy for established nausea or vomiting.

Assessments and statistical analysis

On day 1 and throughout the study, patients used a diary to record emetic episodes, severity ratings of nausea using a 100-mm horizontal visual analogue scale, and any use of rescue therapy (i.e., medication taken for established nausea or vomiting). The sponsor managed the data and performed the analyses, and investigators had access to the data. Gender was a prespecified baseline stratification factor, and the efficacy endpoint for the gender analysis was the proportion of patients with complete response, defined as no emetic episodes and no rescue therapy, in the overall 5-day study period (0–120 h). A modified intent-to-treat approach was used to analyze the data and included all patients who received cisplatin, took study drug, and had at least one posttreatment assessment. A logistic regression model was used to make treatment comparisons for the overall complete response endpoint accounting for gender. Treatment effects were also estimated within each gender for the acute phase (0–24 h) and the delayed phase (24–120 h). Comparisons were also made between treatment groups for the endpoints of no significant nausea (defined as peak visual analogue score <25 mm) and no nausea (peak visual analogue score <5 mm).

No adjustment for multiple comparisons was applied, and p values reported are nominal. Prior to combining the data, the complete response endpoint was analyzed by gender in each study. The direction of the treatment effect was similar between the female and male subgroups in both studies. This fact allowed the combining of data from the two studies and a meaningful interpretation of the results by gender. For evaluation of tolerability in cycle 1, rates of clinical and laboratory adverse events within each gender were tabulated by treatment group. To assess potential differences in treatment response between male and female patients over multiple cycles of chemotherapy, Kaplan–Meier plots were generated for time to first emesis over six cycles in each treatment group, by gender.

Results

Cycle 1

Among the 1,043 patients in the analysis, 435 (42%) were women (42% in the aprepitant group and 43% in the control group). Consistent with female gender as a risk factor for CINV, the rate of overall complete response regardless of treatment group was higher among male patients (61%, n=608) compared with the rate among female patients (53%, n=435). Figure 1 shows percentages of patients with complete response in the overall 5-day study period, by gender and treatment group. For all three time periods evaluated (days 1–5, day 1, days 2–5), when all patients are included, the percentage of patients with complete response (days 1–5) was lower in female patients compared with male patients, confirming that female gender functioned as a risk factor in these studies. Within each gender, patients receiving the aprepitant regimen had a significantly higher response rate compared with patients receiving the control regimen (p<0.001 for each gender group) in the overall 5-day study period. The aprepitant regimen was also superior within each gender in separate comparisons for day 1 (acute phase; Fig. 2) and days 2–5 (delayed phase; Fig. 3). The incremental improvement observed with the addition of aprepitant (i.e., the between-treatment difference) was of greater magnitude in women for all three time periods (25 percentage points for women vs 16 percentage points for men in the overall phase, 20 percentage points for women vs 7 percentage points for men in the acute phase, and 25 percentage points for women vs 17 percentage points for men in the delayed phase).
https://static-content.springer.com/image/art%3A10.1007%2Fs00520-005-0914-4/MediaObjects/520_2005_914_Fig1_HTML.gif
Fig. 1

Percentages of patients with complete response (no emesis and no use of rescue therapy) in the overall 5-day study period of cycle 1, by gender and treatment group. In the aprepitant group, N=520 (women, n=219); in the control group, N=523 (women, n=216)

https://static-content.springer.com/image/art%3A10.1007%2Fs00520-005-0914-4/MediaObjects/520_2005_914_Fig2_HTML.gif
Fig. 2

Percentages of patients with complete response (no emesis and no use of rescue therapy) in the acute phase (0–24 h postcisplatin) of cycle 1, by gender and treatment group. In the aprepitant group, N=520 (women, n=219); in the control group, N=523 (women, n=216)

https://static-content.springer.com/image/art%3A10.1007%2Fs00520-005-0914-4/MediaObjects/520_2005_914_Fig3_HTML.gif
Fig. 3

Percentages of patients with complete response (no emesis and no use of rescue therapy) in the delayed phase (24–120 h postcisplatin) of cycle 1, by gender and treatment group. In the aprepitant group, N=520 (women, n=219); in the control group, N=523 (women, n=216)

In terms of reduction in nausea, the aprepitant regimen was superior in both men and women, with the difference between the aprepitant and control regimens reaching statistical significance among men with no significant nausea (Fig. 4). Regardless of treatment group, men had better nausea protection than women.
https://static-content.springer.com/image/art%3A10.1007%2Fs00520-005-0914-4/MediaObjects/520_2005_914_Fig4_HTML.gif
Fig. 4

Percentages of patients with no nausea and with no significant nausea in cycle 1, by gender and treatment group. No nausea, peak visual analogue score <5 mm; no significant nausea, peak visual analogue score <25 mm

Combined data for multiple cycles

For patients who opted to continue participating in the study beyond cycle 1, time to first emesis over six cycles of chemotherapy was plotted using the Kaplan–Meier method (Fig. 5). Patients taking aprepitant had higher protection rates over all six cycles than patients who did not take aprepitant, regardless of gender. When response rates were compared separately among men and women for each cycle, the between-treatment difference remained in favor of the aprepitant regimen.
https://static-content.springer.com/image/art%3A10.1007%2Fs00520-005-0914-4/MediaObjects/520_2005_914_Fig5_HTML.gif
Fig. 5

Time to first emesis for multiple cycles of chemotherapy, by gender and treatment group. For both genders, the percentage of patients with no emesis at each cycle was superior with aprepitant vs control (p=0.0001 using log-rank test)

Regardless of treatment group, male patients had slightly higher response rates than female patients did over multiple cycles (Fig. 5). Over successive cycles, no-emesis rates declined more quickly in women than in men. Although this divergence occurred in both treatment groups, the between-gender difference tended to be smaller in the aprepitant group than in the control group.

Tolerability

Clinical and laboratory adverse events were reported at very similar rates for both genders and both treatment groups. In the aprepitant group, clinical adverse events were reported in 68% of women and 70% of men, and laboratory events were reported in 21% of women and 23% of men. Similarly, in the control group, clinical adverse events were reported in 67% of women and 67% of men, and laboratory adverse events were reported in 19% of women and 20% of men. Most adverse events were considered by the investigator to be unrelated to study drug.

Discussion

Based on the superior efficacy achieved by adding aprepitant to a standard antiemetic regimen (a 5HT3 antagonist and a corticosteroid) in two large trials with patients receiving cisplatin-based chemotherapy, we assessed combined data from these trials to examine the potential correlations between gender and treatment response. Consistent with historical observations, among patients who received the control regimen of ondansetron and dexamethasone, female patients had distinctly lower rates of response in all three time periods (overall phase, acute phase, and delayed phase) of cycle 1. However, the addition of aprepitant significantly improved response rates not only in the overall study population but also within each gender. The improvements were disproportionate between men and women; the addition of aprepitant improved response rates in women to a greater extent than in men, such that in the aprepitant group, the historically observed difference in treatment response between men and women was virtually eliminated in the initial cycle of chemotherapy.

In terms of nausea, men in both treatment groups had slightly better protection than women did, with the aprepitant group conferring a significant benefit compared with the control regimen in the male subpopulation. Slightly higher rates of protection were also seen with aprepitant among women, suggesting that the aprepitant regimen may provide some enhancement in nausea protection for women as well.

Consistent with previously described results of both a transitional probabilities analysis and a simple comparison of response rates at each cycle [6, 16], the present subanalysis showed that over multiple cycles of chemotherapy, patients taking aprepitant had higher response rates compared with patients taking the control regimen regardless of gender. A similar trend was noted when male and female populations were assessed separately for treatment effect; aprepitant conferred a benefit in both men and women over multiple cycles, and as seen in cycle 1, the magnitude of this benefit was typically greater in women vs men. Among men, the aprepitant group had response rates higher than the control group by an average of 19 percentage points across cycles, whereas among women, response rates with aprepitant were higher by an average of 23 percentage points across cycles. Additionally, the treatments were assessed separately for a potential gender effect. While the response rate by cycle 5 was approximately 15 percentage points higher in males than females regardless of treatment, it was observed that this disparity developed more slowly in patients receiving aprepitant. Among patients taking the control regimen, response rates for men exceeded those for women by 12, 16, 18, 14, and 14 percentage points in cycles 1 through 5, respectively. In contrast, among patients taking aprepitant, the between-gender disparity was less marked and occurred more gradually, with the response rates in males higher by 1, 8, 10, 12, and 15 percentage points in cycles 1 through 5, respectively. Thus, antiemetic protection in women was not as well maintained as in men over multiple cycles, and by cycle 5 appeared to be deficient in both treatment groups to an equivalent degree, but during the intervening cycles, the deficiency was less dramatic in women who received aprepitant. This finding suggests that the greater risk of CINV for women, clearly attenuated by aprepitant in cycle 1, may also have been lessened to some extent by aprepitant through subsequent cycles. The more gradual appearance of between-gender difference over multiple cycles could be due simply to a carryover effect from cycle 1, but previous findings do not favor this explanation, as some patients were emesis-free in later cycles despite having vomited in earlier cycles [6]. Additional studies with larger samples are needed to define these observations more clearly.

The difference in response rates between male and female patients is not well understood, and in fact, gender differences in emetic control are not limited to CINV; in the setting of both postoperative nausea and vomiting and nonoperative opioid administration, women have consistently experienced more nausea and vomiting than men [5, 9, 14, 20, 23]. In the case of CINV, various explanatory hypotheses have been suggested, including hormonal status or chemotherapy-induced endocrine changes [21], as well as potential gender differences in neurotransmitter receptor site distribution, emetic drug binding characteristics [26, 27], or more frequent use in female patients of concomitant moderately emetogenic chemotherapy with cisplatin [22]. In the present studies, randomization was stratified not only for gender but also for use of concomitant chemotherapy. Furthermore, the pharmacokinetic profile of aprepitant has been shown to be similar between men and women [16]. Thus, the difference in response rate more likely reflects some other mechanism, such as an enhanced role of substance P in CINV in females, with a consequently enhanced response to antagonism at the NK1 receptor. In other animal and human studies, gender differences in response to substance P were manifested in various ways, including differences in intestinal mast cell reactivity [3], regulation of NK1-receptor-mediated responses in vagal afferent neurons [15], stress-induced visceral hypersensitivity [4], and analgesic response to kappa-opioids [2]. In the context of this diversity and given the clear findings in the present analysis of the NK1 receptor antagonist aprepitant, a possible gender difference at the NK1 receptor level in CINV is a reasonable speculation.

In summary, the enhanced efficacy of the aprepitant regimen in women during both the acute and delayed phases resulted in similar rates of antiemetic control during cycle 1 for men and women in this analysis of pooled data. Improved protection with aprepitant appeared to be at least partly maintained over multiple cycles for both men and women. In both treatment groups, response rates over multiple cycles decreased more rapidly among women, but somewhat less dramatically in women taking aprepitant. Thus, the aprepitant regimen was not only generally well tolerated and efficacious, but it also reduced the particular risk for CINV to which female patients are known to be susceptible. The finding that the addition of aprepitant to standard care effectively offsets this risk is an unprecedented result and thus may represent a significant step forward in the care of patients who historically have had less reliable antiemetic control than the general population of patients receiving highly emetogenic chemotherapy.

Acknowledgement

This study was funded by Merck and Co., Inc., manufacturer of aprepitant.

Copyright information

© Springer-Verlag 2006