Current Medical Research & Opinion
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0300-7995 doi:10.1185/03007995.2014.925866
2014, 1–7
Article ST-0122.R1/925866 All rights reserved: reproduction in whole or part not permitted
Original article Efficacy of a triple antiemetic regimen with aprepitant for the prevention of chemotherapyinduced nausea and vomiting: effects of gender, age, and region
Bernardo L. Rapoport The Medical Oncology Centre of Rosebank, Johannesburg, South Africa Address for correspondence: Bernardo L. Rapoport MD, Medical Oncologist InCharge, The Medical Oncology Centre of Rosebank, PO Box 2040, Parklands 2121, South Africa. Tel.: +27 11 880 4169; Fax: +27 11 880 4363; [email protected] Keywords: Chemotherapy – Nausea and vomiting – Prevention – Supportive care Accepted: 15 May 2014; published online: 12 June 2014 Citation: Curr Med Res Opin 2014; 1–7
Abstract Objective: To determine the variability in treatment responses to antiemetic therapy (ondansetron and dexamethasone vs ondansetron and dexamethasone plus aprepitant) given with moderately emetogenic chemotherapy. Research design and methods: Post hoc subgroup analysis of data from a phase III, randomized, double-blind clinical trial evaluated whether the efficacy of aprepitant triple therapy (ondansetron and dexamethasone plus aprepitant) versus control (ondansetron and dexamethasone) varies by gender, age, or region in 848 men and women 18 years old with histologically confirmed malignancies and who were naı¨ve to moderately or highly emetogenic chemotherapeutic agents. Endpoints compared were the incidences of no vomiting, complete response, and no use of rescue therapy, all during the overall period (0–120 h). Main outcome measures: Regardless of age, gender, or region, the aprepitant regimen provided better control for the no-vomiting and complete-response (no vomiting, no rescue therapy) endpoints. Results: The aprepitant regimen provided better control for the no-vomiting and complete-response (no vomiting, no rescue therapy) endpoints. Overall response rates were higher in men and in older (55 y) patients, but treatment differences were greater among women and younger patients, known to be at increased chemotherapy-induced nausea and vomiting (CINV) risk. Aprepitant showed a benefit versus control across regions, although the between-treatment difference appeared to be smaller for patients in Central/South America versus North America or international regions. Conclusions: Although we acknowledge that subset numbers in this post hoc analysis may be too small to allow definitive conclusions, the data suggest that aprepitant triple therapy provides a benefit over control therapy for the prevention of CINV in patients receiving anthracycline and cyclophosphamide (AC)- or non-AC-based moderately emetogenic chemotherapy across age, gender, and region. (Original trial results available at ClinicalTrials.gov: NCT00337727.)
Introduction Significant progress has been made in the management of chemotherapyinduced nausea and vomiting (CINV); however, this adverse effect continues ! 2014 Informa UK Ltd www.cmrojournal.com
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to be among the most serious concerns for cancer patients1. Uncontrolled CINV affects patient quality of life, can adversely affect health by causing metabolic and nutritional imbalances, and can reduce compliance and limit the effectiveness of cancer therapy2. Importantly, CINV is associated with increased morbidity, mortality, hospitalization, and utilization of other health care resources3,4. Limited effectiveness related to CINV has been shown to result in worsened outcomes, such as progression of malignancies that are potentially curable4, while improved CINV management is associated with cost savings5. Although the incidence of CINV is determined primarily by the chemotherapeutic regimen used, there are also known risk factors for CINV6,7. Women are particularly susceptible to CINV, as are younger patients (e.g.,550 y). Additional risk factors include susceptibility to motion sickness, history of low alcohol intake, emesis during pregnancy, and previous chemotherapy experience. Aprepitant is a potent, selective, neurokinin-1-receptor antagonist (NK1RA) that has been shown in multiple studies to prevent CINV and generally to be well tolerated8–10. As part of a three-drug regimen, orally administered aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC), as well as for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC)11. Current antiemetic guidelines for MEC depend on the chemotherapy regimen being used. For regimens that include an anthracycline plus cyclophosphamide (AC), guidelines recommend a three-drug regimen that includes an NK1RA (aprepitant) plus a serotonin receptor 5-hydroxytryptamine 3 (5-HT3) antagonist and dexamethasone before chemotherapy, and aprepitant with or without dexamethasone following chemotherapy administration12,13. In addition, the use of aprepitant is recommended by the Multinational Association of Supportive Cancer Care, American Society of Clinical Oncology, National Comprehensive Cancer Network, and European Society for Medical Oncology for the prevention of CINV in all patients receiving HEC2,12,13. A recent multinational, randomized, double-blind trial assessed aprepitant triple therapy in patients with a variety of tumor types receiving a broad range of MEC regimens14. The aprepitant regimen provided a significant improvement over the control regimen (ondansetron and dexamethasone) for complete response (no emetic episodes and no administration of rescue therapy) in the acute, delayed, and overall study phases in patients receiving AC- and non-AC-based MEC. Post hoc analyses of these patients showed that the efficacy of aprepitant varied by tumor type15–17. The most common tumor types evaluated included breast cancer (52%), colorectal cancer (20%), 2
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lung cancer (13%), and gynecological cancers (5.5%; including ovarian cancer [4.6%]). The current post hoc analyses were conducted to determine whether the efficacy of aprepitant varies by gender, age, or region (defined as North America, Central and South America, or international). A better understanding of the antiemetic efficacy of aprepitant-based regimens across these patient groups should aid in providing more individualized therapy, particularly for those known to be at increased risk for CINV with MEC or who are refractory to standard regimens.
Patients and methods The phase III, multinational, prospective, randomized, double-blind, parallel-group trial (ClinicalTrials.gov identifier: NCT00337727) assessed an aprepitant tripletherapy regimen in patients with a variety of tumor types receiving a broad range of MEC regimens14. The study was conducted at sites in the United States, Mexico, Canada, Chile, Brazil, Peru, Colombia, Panama, Hong Kong, Australia, South Africa, France, Germany, Israel, and Russia in accordance with applicable country and local requirements regarding ethics or institutional board committee review. For this post hoc subgroup analysis, the primary study endpoint was the proportion of patients reporting no vomiting during the overall period (0– 120 h) following initiation of cycle 1 of MEC, with a vomiting episode defined as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retches (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were, by definition, separated by the absence of emesis and retching for at least 1 minute. The timing (date and time) of each vomiting episode was recorded by the patient in the diary at the time of occurrence. Secondary endpoints were: (1) the complete response (no vomiting and no use of rescue therapy) during the overall period of cycle 1 of MEC and (2) no use of rescue therapy. Only antiemetic medication that was administered in the context of established nausea and vomiting was considered rescue therapy. These included antidiarrheals, intestinal antiinflammatory/anti-infective agents; antiemetics and antinauseants; drugs for functional gastrointestinal disorders; and antineoplastic agents. Patients recorded in the patient diary the drug, date, and time they took rescue therapy during the overall phase. Detailed information on study endpoints, assessments, and statistical analyses are provided in the full study publication14. Key aspects of the patient population, assessments, and analysis methods are described below. Men and women 18 years of age with histologically confirmed malignancies were eligible for inclusion in the study. All patients were naive to moderately or highly www.cmrojournal.com ! 2014 Informa UK Ltd
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emetogenic chemotherapeutic agents7,12,13 and scheduled to be treated with a single dose of one or more of the following intravenously (IV) administered MEC agents on treatment day 1: any dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin, cyclophosphamide (51500 mg/m2), or cytarabine (41 g/m2). Additional inclusion/exclusion criteria are detailed in the publication of overall study results14. Patients were randomly assigned to one of two treatment groups for antiemetic treatment in conjunction with an initial cycle (cycle 1) of MEC. The aprepitant regimen comprised aprepitant 125 mg orally administered (PO) 1 hour before chemotherapy, ondansetron 8 mg PO 30–60 minutes before chemotherapy and 8 hours after the first dose, and dexamethasone 12 mg PO 30 minutes before chemotherapy, all given on day 1 and followed by aprepitant 80 mg PO once daily on days 2 and 3. The control regimen comprised oral placebo 1 hour before chemotherapy, ondansetron 8 mg PO 30–60 minutes before chemotherapy and 8 hours after the first dose, and dexamethasone 20 mg PO 30 minutes before chemotherapy on day 1, followed by ondansetron 8 mg PO twice daily on days 2 and 3. During the first 120 hours after initiation of chemotherapy, patients recorded the time and date of nausea, vomiting episodes, and use of rescue medication in a diary. Patients assessed nausea daily using a visual analog scale. Presented here are the descriptive results of a post hoc subgroup analysis of the primary endpoint and secondary endpoints across age (555 or 55 y), gender, and region for the overall study period (0–120 h after initiating chemotherapy). For the purposes of this analysis, the regions were defined as North America (United States and Canada), Central and South America (Mexico, Brazil, Panama, Chile, Peru, and Colombia), and international (Hong Kong, Israel, South Africa, Australia, France).
independent ethics committee or institutional review board at each site before patients were allowed to enroll at that site. All patients provided written informed consent before participating in this study.
Statistical analysis
Table 1. Baseline demographics by treatment for age, gender, and region subgroups.
For this investigation, post hoc statistical analyses of the subgroup data were conducted. Ninety-five percent confidence intervals (CIs) are provided for between-treatment differences in the percentage of patients with the response; these analyses were performed using the Miettinen and Nurminen method, an unconditional, asymptotic method18. Significance is indicated when the 95% CI for the between-treatment difference does not contain zero. This study was conducted in accordance with applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. The protocol, its amendments, and the patient informed consent form were reviewed and approved by an ! 2014 Informa UK Ltd www.cmrojournal.com
Results Of 949 patients screened for the overall study, 101 patients (10.6%) were excluded and the remaining 848 patients were randomly assigned to either the aprepitant (n ¼ 430) or control (n ¼ 418) regimen. Reasons for exclusion from the study were ineligibility (n ¼ 66), withdrawn consent (n ¼ 22), deviation from protocol (n ¼ 11), adverse event (n ¼ 1), and trial termination (n ¼ 1)14. The majority of patients were women (n ¼ 652/848, 77%), and the average age of the randomized population was 57 years. Baseline characteristics for the subgroups analyzed – age, gender, and region – were generally balanced across treatment groups and are summarized in Table 1. A full summary of demographic and baseline characteristics, including primary diagnosis and chemotherapy regimen, was reported in the overall study publication14. Regardless of age category, gender, or region, the aprepitant regimen provided better numeric control than the control regimen with respect to the no-vomiting (Table 2) and complete-response (Table 3) endpoints. Proportions of responders for both endpoints were higher in men than in women and in the older versus younger patient subgroups. However, treatment group differences were greater among women and younger patients: of women receiving the aprepitant and control regimen, 72.5% versus 56.7% showed no vomiting, respectively, and 64.5% and 50.3%, respectively, had a complete response. For both no vomiting and complete response, the 95% CI in men did not
Subgroup
Age group, n (%) 555 years 55 years Gender, n (%) Men Women Regiona, n (%) North America Central and South America International
Aprepitant regimen (n ¼ 430)
Control regimen (n ¼ 418)
177 (41.2) 253 (58.8)
192 (45.9) 226 (54.1)
103 (24.0) 327 (76.0)
93 (22.2) 325 (77.8)
73 (17.0) 176 (40.9) 181 (42.1)
78 (18.7) 179 (42.8) 161 (38.5)
a North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation.
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Table 2. Patients with no vomitinga in the overall phase by age, gender, and region subgroups. Subgroup
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Age group, n/N (%) 555 years 55 years Gender, n/N (%) Men Women Regionc, n/N (%) North America Central and South America International
Aprepitant regimen
Control regimen
Differenceb (95% CI for the difference)
124/175 (70.9) 200/250 (80.0)
94/185 (50.8) 158/221 (71.5)
20.1 (10.0, 29.7) 8.5 (0.8, 16.3)
89/101 (88.1) 235/324 (72.5)
71/87 (81.6) 181/319 (56.7)
6.5 (3.8, 17.3) 15.8 (8.4, 23.0)
64/73 (87.7) 119/172 (69.2) 141/180 (78.3)
52/77 (67.5) 105/175 (60.0) 95/154 (61.7)
20.2 (7.0, 33.0) 9.2 (0.9, 19.1) 16.6 (6.9, 26.3)
Full analysis set (N ¼ 832), consisting of those patients who must have taken a dose of study drug, received chemotherapy, and had at least one post-treatment assessment. a No vomiting ¼ no vomiting, retching, or dry heaves. b Difference is defined as aprepitant regimen minus control regimen. c North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation. CI ¼ confidence interval; n ¼ number of patients with desired response; N ¼ number of patients included at the time point.
Table 3. Patients with complete responsea in the overall phase by age, gender, and region subgroups. Subgroup Age group, n/N (%) 555 years 55 years Gender, n/N (%) Men Women Regionc, n/N (%) North America Central and South America International
Aprepitant regimen
Control regimen
Differenceb (95% CI for the difference)
110/175 (62.9) 182/250 (72.8)
82/186 (44.1) 147/221 (66.5)
18.8 (8.5, 28.6) 6.3 (2.0, 14.6)
83/101 (82.2) 209/324 (64.5)
68/87 (78.2) 161/320 (50.3)
4.0 (7.4, 15.8) 14.2 (6.6, 21.7)
51/73 (69.9) 111/172 (64.5) 130/180 (72.2)
40/77 (51.9) 100/176 (56.8) 89/154 (57.8)
18.0 (2.3, 32.7) 7.7 (2.6, 17.8) 14.4 (4.2, 24.5)
Full analysis set (N ¼ 832), consisting of those patients who must have taken a dose of study drug, received chemotherapy, and had at least one post-treatment assessment. a Complete response ¼ no vomiting and no rescue therapy. b Difference is defined as aprepitant regimen minus control regimen. c North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation. CI ¼ confidence interval; n ¼ number of patients with desired response; N ¼ number of patients included at the time point.
show significance (3.8, 17.3 and 7.4, 15.8, respectively). Among younger patients (555 y) receiving the aprepitant and control regimens, 70.9% and 50.8% (95% CI 10.0, 29.7) had no vomiting, respectively, and 62.9% and 44.1% (95% CI 8.5, 28.6) had a complete response. Across regions, the aprepitant regimen showed a benefit over the control regimen for both the no-vomiting and complete response endpoints. However, the difference between treatment groups was apparently smaller for patients in Central and South America and nonsignificant, compared with either North America or the international regions. The proportion of patients achieving the primary endpoint for the aprepitant and control regimens were 87.7% and 67.5% (95% CI 7.0, 33.0) in North America, 69.2% and 60.0% (95% CI 0.9, 19.1) in Central and South America, and 78.3% and 61.7% 4
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(95% CI 6.9, 26.3) in the international regions, respectively. A similar trend was noted for the complete response endpoint. For the no-rescue-therapy endpoint, the gender difference was more apparent than that for age or geographic region (Table 4). For the overall phase of treatment, there was no apparent difference between treatments among men, whereas a higher proportion of women in the aprepitant regimen achieved the no-rescue-therapy endpoint (79.3% vs 71.3% for the control regimen; 95% CI 1.4, 14.7). A pattern similar to that seen for the complete response endpoint across regions was observed: the proportion of patients using no rescue medication was higher in the North America and international regions, with no apparent difference between the treatments in Central and South America. www.cmrojournal.com ! 2014 Informa UK Ltd
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Table 4. Patients with no use of rescue therapy in the overall phase by age, gender, and region subgroups. Subgroup
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Age group, n/N (%) 555 years 55 years Gender, n/N (%) Men Women Regionb, n/N (%) North America Central and South America International
Differencea (95% CI for the difference)
Aprepitant regimen
Control regimen
137/175 (78.3) 209/250 (83.6)
132/186 (71.0) 174/221 (78.7)
7.3 (1.7, 16.2) 4.9 (2.2, 12.1)
89/101 (88.1) 257/324 (79.3)
78/87 (89.7) 228/320 (71.3)
1.6 (10.8, 8.1) 8.0 (1.4, 14.7)
54/73 (74.0) 140/172 (81.4) 152/180 (84.4)
44/77 (57.1) 145/176 (82.4) 117/154 (76.0)
16.9 (1.6, 31.3) 1.0 (9.2, 7.2) 8.4 (0.1, 17.2)
Full analysis set (N ¼ 832), consisting of those patients who must have taken a dose of study drug, received chemotherapy, and had at least one post-treatment assessment. a Difference is defined as aprepitant regimen minus control regimen. b North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation. CI ¼ confidence interval; n ¼ number of patients with desired response; N ¼ number of patients included at the time point.
Discussion Aprepitant has previously been shown to be efficacious and well tolerated across a broad range of cancer patients with varying tumor types receiving MEC or HEC8–10. In addition, the primary analysis of the current study population was the first demonstration of the effectiveness of aprepitant for the acute, delayed, and overall periods in patients receiving non-AC-based MEC14. The current post hoc analyses were conducted to determine whether there was any variation in aprepitant efficacy across subgroups based on age, gender, and region. The results of the current subgroup analysis have confirmed that the aprepitant regimen provided a benefit over a standard regimen regardless of age, gender, or region. It should be noted that the statistical analyses for 95% CI for the betweentreatment differences were post hoc and do not provide direct evidence of whether the subgroup affects the treatment difference. As post hoc analyses, these investigations were not powered for inferential statistics. Therefore, caution should be used in interpreting the 95% CI subgroup analyses; they are not generalizable outside the study population due to the small sample size and the secondary nature of the analyses. Rather, the 95% CIs provide context for statistical significance, indicating a range of 95% certainty of where the true effect lies. Two of the established risk factors for CINV are gender and younger age, with women and younger patients (550 y) at greater risk than men and older patients, respectively6,7. Therefore, it is not surprising that a higher absolute response rate was observed in male patients as well as in older patients for the no vomiting, complete response, and no rescue therapy endpoints. The finding that there was a greater treatment difference within the female and younger subgroups for each of these endpoints suggests that the use of aprepitant with ! 2014 Informa UK Ltd www.cmrojournal.com
MEC may provide an added benefit for these groups of patients at greater risk of emesis. Findings by gender in the current study are similar to those in patients receiving HEC, in that the proportions of males receiving HEC and experiencing overall complete response with either aprepitant plus ondansetron and dexamethasone or ondansetron and dexamethasone were numerically greater than the proportions of females19. Furthermore, the treatment difference within the female subgroup receiving HEC showed that the use of aprepitant positively affected overall complete response compared with the use of ondansetron and dexamethasone alone19. Although the benefit of aprepitant appeared to be maintained across the three regions examined, the between-treatment difference was greater for the North American and international regions compared with Central and South America. It is possible that this difference may reflect a chance finding owing to the examination of relatively small subgroups. However, the finding may reflect differences in management not captured by protocol-defined practices or in tumor type across the regional subgroups. The finding that use of rescue therapy was higher in both treatment groups in Central and South America compared with the other regions suggests the possibility that practice-related differences (e.g., greater tendency to recommend rescue medication or different reimbursement practices) may have diminished betweentreatment differences in that region. Although not addressed in the present study, it is also possible that pharmacogenomic differences across regions could play a role in aprepitant efficacy. Ongoing research has identified a number of genetic polymorphisms, including variants of the serotonin receptor 5-HT3, known to play a role in the pathogenesis in CINV; these allelic differences may contribute to the variable risk of experiencing CINV and response to antiemetic therapy20,21. Aprepitant prevention of CINV by gender, age, region Rapoport
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Polymorphisms on cytochrome P450 enzymes involved in 5-HT3 receptor metabolism also appear to play a role in the disparity in response20,21, and the pattern of these polymorphisms has been shown to differ across regions22. Such variation may be playing a role in the regional differences observed in this study. Further elucidation of a role of genetic polymorphism in the response to CINV treatments and regional dissimilarities in the genes involved should help clinicians further tailor therapeutic needs to the individual patient. The gender, age, and region subgroups have not been further stratified by AC-based and non-AC-based regimens due to the small numbers of patients in such an analysis. However, previous analysis of the data from this study indicated that the aprepitant regimen provided a significant improvement over the control regimen for both AC- and non-AC-based MEC14. Among patients receiving AC-based chemotherapy, complete responses were observed in 68.3% versus 52.9% of patients receiving aprepitant and control regimens, respectively, during the overall phase. Similarly, 83.2% versus 71.3% of patients receiving non-AC-based regimens achieved complete response during the overall phase. The finding that efficacy was maintained across gender is consistent with this finding; patients receiving AC were predominantly women, whereas patients receiving non-AC-based regimens were predominantly men, a finding attributed to the tumor types involved. A pooled analysis of 1872 patients from four randomized, controlled clinical trials23 documented the benefit of the addition of aprepitant to antiemetic regimens in patients receiving platinum chemotherapy agents (cisplatin, carboplatin, or oxaliplatin), although the magnitude of the benefit seen with oxaliplatin was less than that observed with either cisplatin or carboplatin. The observed benefit of an aprepitant triple-therapy regimen across multiple patient subgroups and tumor types, as well as in patients receiving both AC-based and non-AC-based regimens, indicates the broad utility of this regimen. These findings are consistent with the growing evidence that aprepitant provides a benefit across a variety of moderately and highly emetogenic regimens, including more difficult-to-treat patient subsets, and they potentially support broader use of aprepitant than currently indicated in guideline recommendations. Because of the relatively small numbers of specific adverse events, evaluation of safety and tolerability within subgroups was not conducted as part of these analyses. However, in the overall study, consistent with previous aprepitant studies, the aprepitant regimen was generally well tolerated, with a pattern of clinical and laboratory adverse events that was similar to that of the control regimen14. Overall, the incidences of adverse events were similar in the two groups – approximately 6
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63% and 67% for the aprepitant and control regimens, respectively.
Conclusions Results of this post hoc analysis indicate that the addition of aprepitant to an antiemetic regimen of ondansetron and dexamethasone resulted in improved prevention of CINV compared with a standard regimen, for patients receiving MEC regardless of age, gender, or region. These findings lend support to growing evidence for a broad utility of aprepitant triple therapy across a variety of moderately emetic settings, including more difficult-to-treat patient subgroups.
Transparency Declaration of funding Financial support for this study was provided by Merck & Co. Inc., Whitehouse Station, NJ, USA. The author conceived the idea for this post hoc analysis and wrote the manuscript. Declaration of financial/other relationships B.L.R. has disclosed that he has received honoraria for clinical trials, speaker engagements, and advisory boards from Merck & Co. Inc., Whitehouse Station, NJ, USA, in the past 12 months. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments The author thanks Amy Yellen-Shaw PhD, of Complete Healthcare Communications Inc. (Chadds Ford, PA, USA), for writing and editorial assistance during the development of this manuscript. Editorial assistance was also provided by Susan Quin˜ones PhD of Apothecom, Yardley, PA, USA. This assistance was funded by Merck & Co. Inc., Whitehouse Station, NJ, USA. Martha Vollmer MS and Kristen Lewis of Merck & Co. Inc., Whitehouse Station, NJ, USA also provided editorial assistance.
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of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer 2010;18:423-31 Boice J, Brown C, Taylor HJ, et al. Aprepitant in the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapies in patients with gastrointestinal cancer [ESMO GI annual meeting abstract]. Ann Oncol 2009;20(Suppl 2):vii69 Rapoport B, Boice JA, Brown C, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic (MEC) or highly emetogenic (HEC) chemotherapies in patients with lung cancer [EMSO-ECCO meeting abstract P-9048]. Eur J Cancer 2009;7(Suppl 7):519 Webb T, Hardwick J, Carides A, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic (MEC) chemotherapy in patients with breast cancer [SABCS annual meeting abstract]. Cancer Res 2010;69:1116 Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213-26 Hesketh PJ, Grunberg SM, Herrstedt J, et al. 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. Support Care Cancer 2006;14:354-60 Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology (Williston Park) 2004;18:9-14 Rubenstein EB, Slusher BS, Rojas C, Navari RM. New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations. Cancer J 2006;12:341-7 Hammer C, Fasching PA, Loehberg CR, et al. Polymorphism in HTR3D shows different risks for acute chemotherapy-induced vomiting after anthracycline chemotherapy. Pharmacogenomics 2010;11:943-50 Gralla RJ, Rapoport B, Hirdab J, et al. Assessing the magnitude of antiemetic benefit with the addition of the NK1 receptor antagonist (NK1) aprepitant for all platinum agents: analysis of 1,872 patients (pts) in prospective randomized clinical phase III trials (RCTs) [ASCO annual meeting abstract 9057]. J Clin Oncol 2010;20(Suppl 15s):9057
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0300-7995 doi:10.1185/03007995.2014.925866
2014, 1–7
Article ST-0122.R1/925866 All rights reserved: reproduction in whole or part not permitted
Original article Efficacy of a triple antiemetic regimen with aprepitant for the prevention of chemotherapyinduced nausea and vomiting: effects of gender, age, and region
Bernardo L. Rapoport The Medical Oncology Centre of Rosebank, Johannesburg, South Africa Address for correspondence: Bernardo L. Rapoport MD, Medical Oncologist InCharge, The Medical Oncology Centre of Rosebank, PO Box 2040, Parklands 2121, South Africa. Tel.: +27 11 880 4169; Fax: +27 11 880 4363; [email protected] Keywords: Chemotherapy – Nausea and vomiting – Prevention – Supportive care Accepted: 15 May 2014; published online: 12 June 2014 Citation: Curr Med Res Opin 2014; 1–7
Abstract Objective: To determine the variability in treatment responses to antiemetic therapy (ondansetron and dexamethasone vs ondansetron and dexamethasone plus aprepitant) given with moderately emetogenic chemotherapy. Research design and methods: Post hoc subgroup analysis of data from a phase III, randomized, double-blind clinical trial evaluated whether the efficacy of aprepitant triple therapy (ondansetron and dexamethasone plus aprepitant) versus control (ondansetron and dexamethasone) varies by gender, age, or region in 848 men and women 18 years old with histologically confirmed malignancies and who were naı¨ve to moderately or highly emetogenic chemotherapeutic agents. Endpoints compared were the incidences of no vomiting, complete response, and no use of rescue therapy, all during the overall period (0–120 h). Main outcome measures: Regardless of age, gender, or region, the aprepitant regimen provided better control for the no-vomiting and complete-response (no vomiting, no rescue therapy) endpoints. Results: The aprepitant regimen provided better control for the no-vomiting and complete-response (no vomiting, no rescue therapy) endpoints. Overall response rates were higher in men and in older (55 y) patients, but treatment differences were greater among women and younger patients, known to be at increased chemotherapy-induced nausea and vomiting (CINV) risk. Aprepitant showed a benefit versus control across regions, although the between-treatment difference appeared to be smaller for patients in Central/South America versus North America or international regions. Conclusions: Although we acknowledge that subset numbers in this post hoc analysis may be too small to allow definitive conclusions, the data suggest that aprepitant triple therapy provides a benefit over control therapy for the prevention of CINV in patients receiving anthracycline and cyclophosphamide (AC)- or non-AC-based moderately emetogenic chemotherapy across age, gender, and region. (Original trial results available at ClinicalTrials.gov: NCT00337727.)
Introduction Significant progress has been made in the management of chemotherapyinduced nausea and vomiting (CINV); however, this adverse effect continues ! 2014 Informa UK Ltd www.cmrojournal.com
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to be among the most serious concerns for cancer patients1. Uncontrolled CINV affects patient quality of life, can adversely affect health by causing metabolic and nutritional imbalances, and can reduce compliance and limit the effectiveness of cancer therapy2. Importantly, CINV is associated with increased morbidity, mortality, hospitalization, and utilization of other health care resources3,4. Limited effectiveness related to CINV has been shown to result in worsened outcomes, such as progression of malignancies that are potentially curable4, while improved CINV management is associated with cost savings5. Although the incidence of CINV is determined primarily by the chemotherapeutic regimen used, there are also known risk factors for CINV6,7. Women are particularly susceptible to CINV, as are younger patients (e.g.,550 y). Additional risk factors include susceptibility to motion sickness, history of low alcohol intake, emesis during pregnancy, and previous chemotherapy experience. Aprepitant is a potent, selective, neurokinin-1-receptor antagonist (NK1RA) that has been shown in multiple studies to prevent CINV and generally to be well tolerated8–10. As part of a three-drug regimen, orally administered aprepitant is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC), as well as for the prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC)11. Current antiemetic guidelines for MEC depend on the chemotherapy regimen being used. For regimens that include an anthracycline plus cyclophosphamide (AC), guidelines recommend a three-drug regimen that includes an NK1RA (aprepitant) plus a serotonin receptor 5-hydroxytryptamine 3 (5-HT3) antagonist and dexamethasone before chemotherapy, and aprepitant with or without dexamethasone following chemotherapy administration12,13. In addition, the use of aprepitant is recommended by the Multinational Association of Supportive Cancer Care, American Society of Clinical Oncology, National Comprehensive Cancer Network, and European Society for Medical Oncology for the prevention of CINV in all patients receiving HEC2,12,13. A recent multinational, randomized, double-blind trial assessed aprepitant triple therapy in patients with a variety of tumor types receiving a broad range of MEC regimens14. The aprepitant regimen provided a significant improvement over the control regimen (ondansetron and dexamethasone) for complete response (no emetic episodes and no administration of rescue therapy) in the acute, delayed, and overall study phases in patients receiving AC- and non-AC-based MEC. Post hoc analyses of these patients showed that the efficacy of aprepitant varied by tumor type15–17. The most common tumor types evaluated included breast cancer (52%), colorectal cancer (20%), 2
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lung cancer (13%), and gynecological cancers (5.5%; including ovarian cancer [4.6%]). The current post hoc analyses were conducted to determine whether the efficacy of aprepitant varies by gender, age, or region (defined as North America, Central and South America, or international). A better understanding of the antiemetic efficacy of aprepitant-based regimens across these patient groups should aid in providing more individualized therapy, particularly for those known to be at increased risk for CINV with MEC or who are refractory to standard regimens.
Patients and methods The phase III, multinational, prospective, randomized, double-blind, parallel-group trial (ClinicalTrials.gov identifier: NCT00337727) assessed an aprepitant tripletherapy regimen in patients with a variety of tumor types receiving a broad range of MEC regimens14. The study was conducted at sites in the United States, Mexico, Canada, Chile, Brazil, Peru, Colombia, Panama, Hong Kong, Australia, South Africa, France, Germany, Israel, and Russia in accordance with applicable country and local requirements regarding ethics or institutional board committee review. For this post hoc subgroup analysis, the primary study endpoint was the proportion of patients reporting no vomiting during the overall period (0– 120 h) following initiation of cycle 1 of MEC, with a vomiting episode defined as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retches (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes were, by definition, separated by the absence of emesis and retching for at least 1 minute. The timing (date and time) of each vomiting episode was recorded by the patient in the diary at the time of occurrence. Secondary endpoints were: (1) the complete response (no vomiting and no use of rescue therapy) during the overall period of cycle 1 of MEC and (2) no use of rescue therapy. Only antiemetic medication that was administered in the context of established nausea and vomiting was considered rescue therapy. These included antidiarrheals, intestinal antiinflammatory/anti-infective agents; antiemetics and antinauseants; drugs for functional gastrointestinal disorders; and antineoplastic agents. Patients recorded in the patient diary the drug, date, and time they took rescue therapy during the overall phase. Detailed information on study endpoints, assessments, and statistical analyses are provided in the full study publication14. Key aspects of the patient population, assessments, and analysis methods are described below. Men and women 18 years of age with histologically confirmed malignancies were eligible for inclusion in the study. All patients were naive to moderately or highly www.cmrojournal.com ! 2014 Informa UK Ltd
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emetogenic chemotherapeutic agents7,12,13 and scheduled to be treated with a single dose of one or more of the following intravenously (IV) administered MEC agents on treatment day 1: any dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin, cyclophosphamide (51500 mg/m2), or cytarabine (41 g/m2). Additional inclusion/exclusion criteria are detailed in the publication of overall study results14. Patients were randomly assigned to one of two treatment groups for antiemetic treatment in conjunction with an initial cycle (cycle 1) of MEC. The aprepitant regimen comprised aprepitant 125 mg orally administered (PO) 1 hour before chemotherapy, ondansetron 8 mg PO 30–60 minutes before chemotherapy and 8 hours after the first dose, and dexamethasone 12 mg PO 30 minutes before chemotherapy, all given on day 1 and followed by aprepitant 80 mg PO once daily on days 2 and 3. The control regimen comprised oral placebo 1 hour before chemotherapy, ondansetron 8 mg PO 30–60 minutes before chemotherapy and 8 hours after the first dose, and dexamethasone 20 mg PO 30 minutes before chemotherapy on day 1, followed by ondansetron 8 mg PO twice daily on days 2 and 3. During the first 120 hours after initiation of chemotherapy, patients recorded the time and date of nausea, vomiting episodes, and use of rescue medication in a diary. Patients assessed nausea daily using a visual analog scale. Presented here are the descriptive results of a post hoc subgroup analysis of the primary endpoint and secondary endpoints across age (555 or 55 y), gender, and region for the overall study period (0–120 h after initiating chemotherapy). For the purposes of this analysis, the regions were defined as North America (United States and Canada), Central and South America (Mexico, Brazil, Panama, Chile, Peru, and Colombia), and international (Hong Kong, Israel, South Africa, Australia, France).
independent ethics committee or institutional review board at each site before patients were allowed to enroll at that site. All patients provided written informed consent before participating in this study.
Statistical analysis
Table 1. Baseline demographics by treatment for age, gender, and region subgroups.
For this investigation, post hoc statistical analyses of the subgroup data were conducted. Ninety-five percent confidence intervals (CIs) are provided for between-treatment differences in the percentage of patients with the response; these analyses were performed using the Miettinen and Nurminen method, an unconditional, asymptotic method18. Significance is indicated when the 95% CI for the between-treatment difference does not contain zero. This study was conducted in accordance with applicable country or local requirements regarding ethical committee review, informed consent, and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. The protocol, its amendments, and the patient informed consent form were reviewed and approved by an ! 2014 Informa UK Ltd www.cmrojournal.com
Results Of 949 patients screened for the overall study, 101 patients (10.6%) were excluded and the remaining 848 patients were randomly assigned to either the aprepitant (n ¼ 430) or control (n ¼ 418) regimen. Reasons for exclusion from the study were ineligibility (n ¼ 66), withdrawn consent (n ¼ 22), deviation from protocol (n ¼ 11), adverse event (n ¼ 1), and trial termination (n ¼ 1)14. The majority of patients were women (n ¼ 652/848, 77%), and the average age of the randomized population was 57 years. Baseline characteristics for the subgroups analyzed – age, gender, and region – were generally balanced across treatment groups and are summarized in Table 1. A full summary of demographic and baseline characteristics, including primary diagnosis and chemotherapy regimen, was reported in the overall study publication14. Regardless of age category, gender, or region, the aprepitant regimen provided better numeric control than the control regimen with respect to the no-vomiting (Table 2) and complete-response (Table 3) endpoints. Proportions of responders for both endpoints were higher in men than in women and in the older versus younger patient subgroups. However, treatment group differences were greater among women and younger patients: of women receiving the aprepitant and control regimen, 72.5% versus 56.7% showed no vomiting, respectively, and 64.5% and 50.3%, respectively, had a complete response. For both no vomiting and complete response, the 95% CI in men did not
Subgroup
Age group, n (%) 555 years 55 years Gender, n (%) Men Women Regiona, n (%) North America Central and South America International
Aprepitant regimen (n ¼ 430)
Control regimen (n ¼ 418)
177 (41.2) 253 (58.8)
192 (45.9) 226 (54.1)
103 (24.0) 327 (76.0)
93 (22.2) 325 (77.8)
73 (17.0) 176 (40.9) 181 (42.1)
78 (18.7) 179 (42.8) 161 (38.5)
a North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation.
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Table 2. Patients with no vomitinga in the overall phase by age, gender, and region subgroups. Subgroup
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Age group, n/N (%) 555 years 55 years Gender, n/N (%) Men Women Regionc, n/N (%) North America Central and South America International
Aprepitant regimen
Control regimen
Differenceb (95% CI for the difference)
124/175 (70.9) 200/250 (80.0)
94/185 (50.8) 158/221 (71.5)
20.1 (10.0, 29.7) 8.5 (0.8, 16.3)
89/101 (88.1) 235/324 (72.5)
71/87 (81.6) 181/319 (56.7)
6.5 (3.8, 17.3) 15.8 (8.4, 23.0)
64/73 (87.7) 119/172 (69.2) 141/180 (78.3)
52/77 (67.5) 105/175 (60.0) 95/154 (61.7)
20.2 (7.0, 33.0) 9.2 (0.9, 19.1) 16.6 (6.9, 26.3)
Full analysis set (N ¼ 832), consisting of those patients who must have taken a dose of study drug, received chemotherapy, and had at least one post-treatment assessment. a No vomiting ¼ no vomiting, retching, or dry heaves. b Difference is defined as aprepitant regimen minus control regimen. c North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation. CI ¼ confidence interval; n ¼ number of patients with desired response; N ¼ number of patients included at the time point.
Table 3. Patients with complete responsea in the overall phase by age, gender, and region subgroups. Subgroup Age group, n/N (%) 555 years 55 years Gender, n/N (%) Men Women Regionc, n/N (%) North America Central and South America International
Aprepitant regimen
Control regimen
Differenceb (95% CI for the difference)
110/175 (62.9) 182/250 (72.8)
82/186 (44.1) 147/221 (66.5)
18.8 (8.5, 28.6) 6.3 (2.0, 14.6)
83/101 (82.2) 209/324 (64.5)
68/87 (78.2) 161/320 (50.3)
4.0 (7.4, 15.8) 14.2 (6.6, 21.7)
51/73 (69.9) 111/172 (64.5) 130/180 (72.2)
40/77 (51.9) 100/176 (56.8) 89/154 (57.8)
18.0 (2.3, 32.7) 7.7 (2.6, 17.8) 14.4 (4.2, 24.5)
Full analysis set (N ¼ 832), consisting of those patients who must have taken a dose of study drug, received chemotherapy, and had at least one post-treatment assessment. a Complete response ¼ no vomiting and no rescue therapy. b Difference is defined as aprepitant regimen minus control regimen. c North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation. CI ¼ confidence interval; n ¼ number of patients with desired response; N ¼ number of patients included at the time point.
show significance (3.8, 17.3 and 7.4, 15.8, respectively). Among younger patients (555 y) receiving the aprepitant and control regimens, 70.9% and 50.8% (95% CI 10.0, 29.7) had no vomiting, respectively, and 62.9% and 44.1% (95% CI 8.5, 28.6) had a complete response. Across regions, the aprepitant regimen showed a benefit over the control regimen for both the no-vomiting and complete response endpoints. However, the difference between treatment groups was apparently smaller for patients in Central and South America and nonsignificant, compared with either North America or the international regions. The proportion of patients achieving the primary endpoint for the aprepitant and control regimens were 87.7% and 67.5% (95% CI 7.0, 33.0) in North America, 69.2% and 60.0% (95% CI 0.9, 19.1) in Central and South America, and 78.3% and 61.7% 4
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(95% CI 6.9, 26.3) in the international regions, respectively. A similar trend was noted for the complete response endpoint. For the no-rescue-therapy endpoint, the gender difference was more apparent than that for age or geographic region (Table 4). For the overall phase of treatment, there was no apparent difference between treatments among men, whereas a higher proportion of women in the aprepitant regimen achieved the no-rescue-therapy endpoint (79.3% vs 71.3% for the control regimen; 95% CI 1.4, 14.7). A pattern similar to that seen for the complete response endpoint across regions was observed: the proportion of patients using no rescue medication was higher in the North America and international regions, with no apparent difference between the treatments in Central and South America. www.cmrojournal.com ! 2014 Informa UK Ltd
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Table 4. Patients with no use of rescue therapy in the overall phase by age, gender, and region subgroups. Subgroup
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Age group, n/N (%) 555 years 55 years Gender, n/N (%) Men Women Regionb, n/N (%) North America Central and South America International
Differencea (95% CI for the difference)
Aprepitant regimen
Control regimen
137/175 (78.3) 209/250 (83.6)
132/186 (71.0) 174/221 (78.7)
7.3 (1.7, 16.2) 4.9 (2.2, 12.1)
89/101 (88.1) 257/324 (79.3)
78/87 (89.7) 228/320 (71.3)
1.6 (10.8, 8.1) 8.0 (1.4, 14.7)
54/73 (74.0) 140/172 (81.4) 152/180 (84.4)
44/77 (57.1) 145/176 (82.4) 117/154 (76.0)
16.9 (1.6, 31.3) 1.0 (9.2, 7.2) 8.4 (0.1, 17.2)
Full analysis set (N ¼ 832), consisting of those patients who must have taken a dose of study drug, received chemotherapy, and had at least one post-treatment assessment. a Difference is defined as aprepitant regimen minus control regimen. b North America ¼ United States and Canada; Central and South America ¼ Mexico, Brazil, Panama, Chile, Peru, Colombia; International ¼ Hong Kong, Israel, South Africa, Australia, France, Germany, Russian Federation. CI ¼ confidence interval; n ¼ number of patients with desired response; N ¼ number of patients included at the time point.
Discussion Aprepitant has previously been shown to be efficacious and well tolerated across a broad range of cancer patients with varying tumor types receiving MEC or HEC8–10. In addition, the primary analysis of the current study population was the first demonstration of the effectiveness of aprepitant for the acute, delayed, and overall periods in patients receiving non-AC-based MEC14. The current post hoc analyses were conducted to determine whether there was any variation in aprepitant efficacy across subgroups based on age, gender, and region. The results of the current subgroup analysis have confirmed that the aprepitant regimen provided a benefit over a standard regimen regardless of age, gender, or region. It should be noted that the statistical analyses for 95% CI for the betweentreatment differences were post hoc and do not provide direct evidence of whether the subgroup affects the treatment difference. As post hoc analyses, these investigations were not powered for inferential statistics. Therefore, caution should be used in interpreting the 95% CI subgroup analyses; they are not generalizable outside the study population due to the small sample size and the secondary nature of the analyses. Rather, the 95% CIs provide context for statistical significance, indicating a range of 95% certainty of where the true effect lies. Two of the established risk factors for CINV are gender and younger age, with women and younger patients (550 y) at greater risk than men and older patients, respectively6,7. Therefore, it is not surprising that a higher absolute response rate was observed in male patients as well as in older patients for the no vomiting, complete response, and no rescue therapy endpoints. The finding that there was a greater treatment difference within the female and younger subgroups for each of these endpoints suggests that the use of aprepitant with ! 2014 Informa UK Ltd www.cmrojournal.com
MEC may provide an added benefit for these groups of patients at greater risk of emesis. Findings by gender in the current study are similar to those in patients receiving HEC, in that the proportions of males receiving HEC and experiencing overall complete response with either aprepitant plus ondansetron and dexamethasone or ondansetron and dexamethasone were numerically greater than the proportions of females19. Furthermore, the treatment difference within the female subgroup receiving HEC showed that the use of aprepitant positively affected overall complete response compared with the use of ondansetron and dexamethasone alone19. Although the benefit of aprepitant appeared to be maintained across the three regions examined, the between-treatment difference was greater for the North American and international regions compared with Central and South America. It is possible that this difference may reflect a chance finding owing to the examination of relatively small subgroups. However, the finding may reflect differences in management not captured by protocol-defined practices or in tumor type across the regional subgroups. The finding that use of rescue therapy was higher in both treatment groups in Central and South America compared with the other regions suggests the possibility that practice-related differences (e.g., greater tendency to recommend rescue medication or different reimbursement practices) may have diminished betweentreatment differences in that region. Although not addressed in the present study, it is also possible that pharmacogenomic differences across regions could play a role in aprepitant efficacy. Ongoing research has identified a number of genetic polymorphisms, including variants of the serotonin receptor 5-HT3, known to play a role in the pathogenesis in CINV; these allelic differences may contribute to the variable risk of experiencing CINV and response to antiemetic therapy20,21. Aprepitant prevention of CINV by gender, age, region Rapoport
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Polymorphisms on cytochrome P450 enzymes involved in 5-HT3 receptor metabolism also appear to play a role in the disparity in response20,21, and the pattern of these polymorphisms has been shown to differ across regions22. Such variation may be playing a role in the regional differences observed in this study. Further elucidation of a role of genetic polymorphism in the response to CINV treatments and regional dissimilarities in the genes involved should help clinicians further tailor therapeutic needs to the individual patient. The gender, age, and region subgroups have not been further stratified by AC-based and non-AC-based regimens due to the small numbers of patients in such an analysis. However, previous analysis of the data from this study indicated that the aprepitant regimen provided a significant improvement over the control regimen for both AC- and non-AC-based MEC14. Among patients receiving AC-based chemotherapy, complete responses were observed in 68.3% versus 52.9% of patients receiving aprepitant and control regimens, respectively, during the overall phase. Similarly, 83.2% versus 71.3% of patients receiving non-AC-based regimens achieved complete response during the overall phase. The finding that efficacy was maintained across gender is consistent with this finding; patients receiving AC were predominantly women, whereas patients receiving non-AC-based regimens were predominantly men, a finding attributed to the tumor types involved. A pooled analysis of 1872 patients from four randomized, controlled clinical trials23 documented the benefit of the addition of aprepitant to antiemetic regimens in patients receiving platinum chemotherapy agents (cisplatin, carboplatin, or oxaliplatin), although the magnitude of the benefit seen with oxaliplatin was less than that observed with either cisplatin or carboplatin. The observed benefit of an aprepitant triple-therapy regimen across multiple patient subgroups and tumor types, as well as in patients receiving both AC-based and non-AC-based regimens, indicates the broad utility of this regimen. These findings are consistent with the growing evidence that aprepitant provides a benefit across a variety of moderately and highly emetogenic regimens, including more difficult-to-treat patient subsets, and they potentially support broader use of aprepitant than currently indicated in guideline recommendations. Because of the relatively small numbers of specific adverse events, evaluation of safety and tolerability within subgroups was not conducted as part of these analyses. However, in the overall study, consistent with previous aprepitant studies, the aprepitant regimen was generally well tolerated, with a pattern of clinical and laboratory adverse events that was similar to that of the control regimen14. Overall, the incidences of adverse events were similar in the two groups – approximately 6
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63% and 67% for the aprepitant and control regimens, respectively.
Conclusions Results of this post hoc analysis indicate that the addition of aprepitant to an antiemetic regimen of ondansetron and dexamethasone resulted in improved prevention of CINV compared with a standard regimen, for patients receiving MEC regardless of age, gender, or region. These findings lend support to growing evidence for a broad utility of aprepitant triple therapy across a variety of moderately emetic settings, including more difficult-to-treat patient subgroups.
Transparency Declaration of funding Financial support for this study was provided by Merck & Co. Inc., Whitehouse Station, NJ, USA. The author conceived the idea for this post hoc analysis and wrote the manuscript. Declaration of financial/other relationships B.L.R. has disclosed that he has received honoraria for clinical trials, speaker engagements, and advisory boards from Merck & Co. Inc., Whitehouse Station, NJ, USA, in the past 12 months. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments The author thanks Amy Yellen-Shaw PhD, of Complete Healthcare Communications Inc. (Chadds Ford, PA, USA), for writing and editorial assistance during the development of this manuscript. Editorial assistance was also provided by Susan Quin˜ones PhD of Apothecom, Yardley, PA, USA. This assistance was funded by Merck & Co. Inc., Whitehouse Station, NJ, USA. Martha Vollmer MS and Kristen Lewis of Merck & Co. Inc., Whitehouse Station, NJ, USA also provided editorial assistance.
References 1. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer 2005;13:219-27 2. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology – V.2.2010: Antiemesis. Available at: https://www.nccn.org/ store/login/login.aspx?ReturnURL=http://www.nccn.org/professionals/ physician_gls/pdf/antiemesis.pdf. Last accessed 2 June 2014 3. Ihbe-Heffinger A, Ehlken B, Bernard R, et al. The impact of delayed chemotherapy-induced nausea and vomiting on patients, health resource utilization and costs in German cancer centers. Ann Oncol 2004;15:526-36 4. Neymark N, Crott R. Impact of emesis on clinical and economic outcomes of cancer therapy with highly emetogenic chemotherapy regimens: a
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