VOLUME
32
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30
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OCTOBER
20
2014
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Aprepitant, Granisetron, and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting After High-Dose Melphalan in Autologous Transplantation for Multiple Myeloma: Results of a Randomized, Placebo-Controlled Phase III Trial Thomas Schmitt, Hartmut Goldschmidt, Kai Neben, Anja Freiberger, Johannes Hu¨sing, Martina Gronkowski, Markus Thalheimer, Le Hang Pelzl, Gerd Mikus, Ju¨rgen Burhenne, Anthony D. Ho, and Gerlinde Egerer Thomas Schmitt, Hartmut Goldschmidt, Anja Freiberger, Johannes Hu¨sing, Martina Gronkowski, Markus Thalheimer, Le Hang Pelzl, Gerd Mikus, Ju¨rgen Burhenne, Anthony D. Ho, and Gerlinde Egerer, Heidelberg University Hospital, Heidelberg; and Kai Neben, Klinikum Mittelbaden, Baden-Baden, Germany. Published online ahead of print at www.jco.org on September 15, 2014. Supported by Merck Sharp & Dohme (Germany). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00571168. Corresponding author: Thomas Schmitt, MD, Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology
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Purpose The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients and Methods Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m2 was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index–Emesis (FLIE) questionnaire on days ⫺1 and 6. Results Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P ⫽ .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P ⫽ .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P ⫽ .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (⫾ standard deviation) was 114 ⫾ 18 for aprepitant and 106 ⫾ 26 for placebo (P ⬍ .001). Conclusion The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life. J Clin Oncol 32:3413-3420. © 2014 by American Society of Clinical Oncology
0732-183X/14/3230w-3413w/$20.00 DOI: 10.1200/JCO.2013.55.0095
INTRODUCTION
Nausea and vomiting can severely affect the quality of life of patients receiving chemotherapy and are some of the most dreaded adverse effects.1 Incidence, prevalence, and severity of chemotherapyinduced nausea and vomiting (CINV) are related to several factors, most notably the emetic potential of the chemotherapy itself and patients’ individual risk factors. Because of the implementation of riskadapted prophylaxis and treatment guidelines, incidence of CINV has been reduced substantially.2,3 The most important agents used in clinical
practice today include 5-hydroxytryptamine-3 (5-HT3; serotonin) antagonists, corticosteroids, and neurokinin-1 (NK-1) antagonists. Aprepitant (Emend; Merck, Whitehouse Station, NJ) was the first NK-1 antagonist introduced into clinical care in 2003.4-7 Although classical 5-HT3 antagonists are especially effective in prevention of acute emesis (onset ⬍ 24 hours after chemotherapy administration), NK-1 antagonists and corticosteroids improve control of acute and delayed emesis (onset ⬎ 24 hours after chemotherapy administration). Effect of NK-1 antagonists is pronounced in delayed phase. © 2014 by American Society of Clinical Oncology
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In patients with multiple myeloma age ⬍ 70 years, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care.8,9 Although melphalan, the conditioning agent commonly used in this setting, is generally regarded as only moderately emetogenic, CINV can be significant and distressing. Historic reports before use of 5-HT3 antagonists note almost universal emesis.10,11 Overall, data on the optimal strategy for prevention of CINV in ASCT are scarce, and current American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC) guidelines recommend the combination of dexamethasone and a 5-HT3 antagonist.2,3 An NK-1 antagonist can be considered, although data supporting its use are limited, because larger prospective trials are missing and/or combine heterogeneous patient populations, conditioning regimens, and autologous as well as allogeneic transplantations.12 Here we report the results of a prospective, randomized, placebo-controlled trial of aprepitant, granisetron, and dexamethasone in patients with multiple myeloma undergoing high-dose melphalan conditioning. PATIENTS AND METHODS Trial Design This protocol was designed as a prospective, placebo-controlled, randomized, double-blind, parallel-group, single-center study conducted at the Heidelberg University Hospital (Heidelberg, Germany). Currently, we perform approximately 200 autologous transplantations at our center per year, making it the largest program in Germany. Written informed consent was obtained from all patients before trial participation. A computer-generated randomization list (SAS PLAN; SAS Institute, Cary, NC) was used to allocate treatment codes on a one-to-one basis for the two treatment arms. This task was conducted at the Coordination Centre for Clinical Trials (KKS; Heidelberg, Germany) independent of all other trial procedures. The trial was carried out according to good clinical practice and the principles stated in the Declaration of Helsinki in 1964, as well as all subsequent revisions. The study protocol was approved by the institutional ethics committee and the competent authority (Bundesinstitut fu¨r Arzneimittel und Medizinprodukte, Bonn, Germany; EudraCT-No. 2004004956-38). Inclusion and Exclusion Criteria All patients (age ⱖ 18 years) with multiple myeloma undergoing autologous transplantation after high-dose melphalan conditioning were eligible for participation. Exclusion criteria were as follows: nausea or vomiting within 12 hours before planned high-dose chemotherapy, any antiemetic treatment within 24 hours before planned high-dose chemotherapy, intake of corticosteroids, and known hypersensitivity to the investigational product. All enrolled patients received a randomization number identifying him or her throughout the course of the trial. Study Treatment Trial duration for each individual patient included a treatment phase of 4 days (days 1 to 4) and follow-up phase of 3 days (days 5 to 7). Patients were randomly assigned at a one-to-one ratio to receive either aprepitant 125 mg orally on day 1 and 80 mg orally on days 2 to 4, granisetron 2 mg orally on days 1 to 4, and dexamethasone 4 mg orally on day 1 and 2 mg orally on days 2 to 3 or matching placebo orally on days 1 to 4, granisetron 2 mg orally on days 1 to 4, and dexamethasone 8 mg orally on day 1 and 4 mg orally on days 2 to 3 (Table 1). To reduce the risk of infection after ASCT, a lower dose of dexamethasone than generally recommended for highly emetogenic regimens was chosen. Furthermore, according to the summary of product characteristics of aprepitant, the dose of dexametha3414
© 2014 by American Society of Clinical Oncology
Table 1. Treatment Schedule Melphalan 100 mg/m2 (day) Regimen Arm A Aprepitant, mg Granisetron, mg Dexamethasone, mg Arm B Placebo, mg Granisetron, mg Dexamethasone, mg
ASCT (day)
1
2
3
4
125 2 4
80 2 2
80 2 2
80 2
125 2 8
80 2 4
80 2 4
80 2
Abbreviation: ASCT, autologous stem-cell transplantation.
sone was reduced by 50% when coadministered. Study medication was manufactured, labeled, and packed by the pharmacy department of the Heidelberg University Hospital according to the randomization list. Appearance and dosage of aprepitant, placebo, and dexamethasone were double blinded in both treatment arms. Aprepitant/placebo and granisetron/dexamethasone were administered 60 and 30 minutes before administration of melphalan (100 mg/m2 intravenously on days 1 to 2), respectively. Rescue medication for breakthrough CINV was left up to the treating physician. Study End Points The primary end point of this study was overall complete response, defined as no emesis and no rescue therapy within 120 hours of melphalan administration. The time interval of 120 hours was chosen because it can be assumed that additional cofactors (eg, mucositis and antibiotic use) influence rates of nausea and vomiting after this point in time. Preplanned secondary end points included complete response, defined as no emesis and no rescue therapy in acute (0 to 24 hours) or delayed phase (25 to 120 hours), rates of emesis, nausea and significant nausea, number of adverse events, and impact on quality of daily life, as assessed by modified Functional Living Index–Emesis (FLIE) score. Assessment Patients were asked to complete a diary on a daily basis recording episodes of vomiting (vomits and/or dry heaves) and presence or absence of nausea and its severity on a 100-mm visual analog scale (VAS). No nausea was defined as VAS ⬍ 5 mm and significant nausea as VAS ⬎ 25 mm. Furthermore, rescue therapy was recorded over a period of 5 days. A FLIE questionnaire with a 5-day recall was completed on day ⫺1 for baseline assessment and training and on the morning of day 6.13 No impact on daily life was defined as an average FLIE item score ⬎ 6 on the 7-point scale (or respectively, total score ⱖ 108). Adverse events were recorded on days 1 to 7, and safety laboratory evaluations (CBC and coagulation, renal, and liver function tests) were performed during screening and on days 4 and 7. Adverse events were recorded according to Common Terminology Criteria for Adverse Events (version 3.0) and further graded by the principal investigator as mild (temporary event well tolerated by patient), moderate (event resulting in discomfort for patient and impairing normal daily activity), or severe (event resulting in substantial impairment of normal daily activity). Statistical Analyses The necessary study sample size (N ⫽ 362) was calculated with respect to a 2 test of the primary end point, the proportion of overall complete response. The test was carried out for the two-sided null hypothesis of no difference in proportion. A difference in proportion of at least 15% (65% v 50%) was determined to cause a significant effect (at .05 level), with a power of 0.80. A preplanned interim analysis was performed after the inclusion of 180 patients at a level of .01, and the final analysis was JOURNAL OF CLINICAL ONCOLOGY
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EMNA Study
performed after 362 patients at a level of .04, maintaining an overall level of .05. Efficacy end points were analyzed following a strict intention-to-treat (ITT) approach, as recommended in International Conference on Harmonisation E9 guidelines. All analyses of the primary end point were based on logistic regression models, including the impact of previous CINV and sex as explanatory variables. Rates of emesis were modeled using a timeto-event model allowing multiple events per patient, following the Andersen-Gill multiplicative hazards model. Assumptions of proportionality over time for treatment covariates were checked. To give an idea about the extent of emesis, mean waiting time to next emesis event was roughly estimated by dividing total time patients were observed by number of events in each group. Treatments were compared with respect to all other dichotomous variables using 2 tests and uncorrected CIs, and effects were presented as odds ratios (ORs). Difference in FLIE score between treatment arms was assessed by t test. No advanced algorithm to replace missing values was applied, because there was a high level of completeness. All analyses were prespecified in a statistical analysis plan, which was completed before the database was unblinded. Only the primary analysis was controlled for type I error; therefore, analyses of secondary parameters should be viewed as exploratory. The plan was updated after interim analysis, but the updates did not affect any procedures performed in the interim analysis. J.H. (KKS) performed all statistical analyses. For data management and statistical testing, SAS software (version 9.3) was used.
RESULTS
Between July 2005 and January 2012, a total of 609 patients with multiple myeloma undergoing high-dose melphalan therapy and ASCT were screened, and 363 were randomly assigned. Four patients underwent double ASCT and were excluded from participating twice. One patient was randomly assigned but found to have plasma cell leukemia before receiving study medication and was therefore excluded from the efficacy analysis. Therefore, 181 patients were randomly assigned to aprepitant and 181 to placebo and were available for ITT analysis. Overall, 36 and 46 patients in the treatment and placebo arms, respectively, were excluded from per-protocol (PP) analysis for not meeting eligibility criteria, not receiving melphalan within the required timeframe after intake of study medication, receiving additional antiemetic medication, and/or having problems with the FLIE questionnaire. The PP set thus comprised 145 and 135 patients in the aprepitant and placebo arms, respectively. A CONSORT diagram is shown in Figure 1.14 All patients completed at least 96 of 120 hours postrandomization. Sex and age distributions were well balanced between both arms. In three patient cases, no information on prior CINV was obtained; these were treated as if there had been none. Patient characteristics are summarized in Table 2. Efficacy Analyses An interim analysis for the primary end point was performed after inclusion of 180 patients. Statistical testing failed to prove a difference between the two treatment arms at a significance level of .01 (OR, 1.60; P ⫽ .15). Therefore, the study was continued until accrual of 362 patients. In the ITT population, significantly more patients receiving aprepitant reported no emesis and no additional antiemetic treatment within 120 hours of melphalan administration (overall complete response) compared with placebo (58% v 41%; OR, 1.92; 95% CI, 1.23 to 3.00; P ⫽ .0042). As expected, the overall effect was more pronounced in the PP analysis (59% v 39%; OR, 2.16; 95% CI, 1.30 to 3.60; P ⫽ .003). www.jco.org
No emesis or additional antiemetic treatment in the acute phase (⬍ 24 hours after melphalan administration) was reported by 97% and 90% of patients receiving aprepitant and placebo, respectively (OR, 3.11; 95% CI, 1.23 to 8.92; P ⫽ .022). During the delayed phase (24 to 120 hours after melphalan administration), this was achieved in 60% and 46% of patients, respectively (OR, 1.80; 95% CI, 1.15 to 2.85; P ⫽ .011), suggesting a lasting benefit after 24 hours (Fig 2). Major nausea was prevented in 94% and 88% of patients in the aprepitant and placebo arms, respectively (OR, 2.37; 95% CI, 1.09 to 5.15; P ⫽ .026). Effect on overall nausea (85% v 78%; OR, 1.55; 95% CI, 0.91 to 2.65; P ⫽ .106) was less pronounced. Absence of emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P ⫽ .0036) within 120 hours of melphalan administration was increased for patients receiving aprepitant. Mean time to next episode of emesis was prolonged from 4.8 (placebo) to 7.4 days (aprepitant), with a resulting relative rate of 0.65 (95% CI, 0.50 to 0.83; P ⬍ .001). Effect on necessity for rescue medication for the entire study period of 7 days was less salient (48% v 40%; OR, 1.34; 95% CI, 0.88 to 2.03; P ⫽ .169). Analysis of quality of life was based on a complete case approach. A total of 356 patients completed the questionnaire by protocol; 74% of those receiving aprepitant, compared with 59% of patients receiving placebo, had an FLIE score indicating no impact on daily life (P ⫽ .004). Mean total FLIE score (⫾ standard deviation) was 114 ⫾ 18 for those receiving aprepitant and 106 ⫾ 26 points for those receiving placebo (P ⬍ .001). Efficacy data are summarized in Table 3. Safety Analysis Rates of adverse events did not significantly differ between the two treatment arms. Intensity of the reported adverse events was mild (64% v 64%), moderate (32% v 34%), and severe (3% v 3%) for aprepitant and placebo, respectively. The most frequently observed adverse events (aprepitant v placebo) were leukopenia (mild, 10% v 10%; moderate, 49% v 51%; severe, 18% v 15%), hypocalcemia (mild, 45% v 46%; moderate, 3% v 2%), fatigue (mild, 34% v 29%; moderate, 27% v 29%), edema (mild, 41% v 38%; moderate, 8% v 8%), and constipation (mild, 25% v 28%; moderate, 10% v 9%). Six patients terminated the study prematurely (two in aprepitant arm; four in placebo arm); reasons were lack of compliance (placebo, n ⫽ 2), uncontrollable emesis (placebo, n ⫽ 1), seizure (aprepitant, n ⫽ 1), and short-term change of conditioning regimen (placebo, n ⫽ 1). One patient in the aprepitant arm died during study participation, most likely as a result of dimethyl sulfoxide (DSMO) –induced encephalopathy. DMSO is an agent used for cryopreservation of hematopoetic stem cells at our center. Cause of death was considered unrelated to study medication. DISCUSSION
Nausea and vomiting are some of the most distressing adverse effects for patients undergoing chemotherapy. However, the optimal prophylactic regimen for patients receiving high-dose chemotherapy and ASCT is still unknown, and available data are limited. Current ASCO and ESMO/MASCC guidelines recommend the combination of a 5-HT3 antagonist and dexamethasone.2,3 With © 2014 by American Society of Clinical Oncology
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Schmitt et al
Screened (N = 609)
Excluded (n = 246) Participation (n = 131) declined High-dose therapy (n = 30) other than melphalan Contraindications (n = 59) Previous participation (n = 4) in same trial Participation in (n = 12) other trial Other reasons (n = 10)
Randomly assigned (n = 363)
Aprepitant (n = 182)
Placebo (n = 181)
Did not receive study medication (n = 1)
Did not receive study medication (n = 0) Full analysis set (n = 181)
Excluded from perprotocol analysis Eligibility criteria violated Administration of melphalan outside time frame Completion of FLIE not by patient
Full analysis set (n = 181) Excluded from perprotocol analysis Eligibility criteria violated Additional antiemetics Administration of melphalan outside time frame Completion of FLIE not by patient Delayed completion of FLIE
(n = 36)* (n = 4) (n = 33)
(n = 4)
Per-protocol set (n = 145)
(n = 46)* (n = 2) (n = 1) (n = 40)
(n = 2) (n = 2)
Per-protocol set (n = 135)
Fig 1. CONSORT diagram. FLIE, Functional Living Index–Emesis. (*) Multiple reasons for exclusion per patient may apply.
this standard prophylactic regimen, it can be hypothesized that 70% to 80% of patients have effective control of acute CINV.15-17 However, a majority of patients will experience delayed CINV. Here we report the results of our phase IIIb trial of granisetron, dexamethasone, and aprepitant for patients with multiple myeloma undergoing high-dose melphalan conditioning and ASCT. To our knowledge, this is the largest prospective, randomized phase III trial assessing this question. The combination regimen resulted in a significant reduction of major nausea and emesis. In the ITT population, no emesis and no antiemetic rescue medication within 120 hours of melphalan administration (overall phase) were reported for 58% and 41% of patients receiving aprepitant and placebo, respectively (OR, 1.92; 95% CI, 1.23 to 3.00; P ⫽ .0042); the effect in the PP set was slightly pronounced 3416
© 2014 by American Society of Clinical Oncology
(59% v 39%; OR, 2.16; 95% CI, 1.30 to 3.60; P ⫽ .003). The majority of patients excluded from the PP analysis did not receive the melphalan infusion within the required timeframe after intake of study medication. Thus, it can be speculated that suboptimal drug plasma levels at least influenced rates of acute CINV. However, the overall effect seemed to be negligible. Tests regarding proportionality of hazards revealed that treatment effects converged with time. This could have led to underestimation of treatment effect, but we opted against diverging from the analysis plan with respect to the primary end point.18 Rates of adverse events between the treatment arms did not differ, and melphalan pharmacokinetics were not altered by concomitant aprepitant administration (results reported elsewhere).19 Quality of life as assessed by FLIE questionnaire was improved significantly. JOURNAL OF CLINICAL ONCOLOGY
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EMNA Study
Table 3. Efficacy Data: Secondary End Points
Table 2. Patient Demographic and Clinical Characteristics Aprepitant Arm Characteristic Sex Male Female Age, years Median Range Previous CINV None Light Moderate Severe Not available
Efficacy End Point Placebo Arm
All Patients
No.
%
No.
%
No.
%
120 61
66 34
110 71
61 39
230 132
64 36
58.3 27-72 100 41 32 6 2
57.9 35-72 55 23 18 3 1
85 47 28 19 2
58.1
47 26 15 11 1
185 88 60 25 4
51 24 17 7 1
Abbreviation: CINV, chemotherapy-induced nausea and vomiting.
Direct comparison of our results with literature is complicated by different definitions of the primary end point, the mostly retrospective character of the published results, and the diversity of disease-specific conditioning regimens with varying emetic potential (Table 4). The largest prospective trial so far was reported by Stiff et al,12 showing no emesis with no or only mild nausea in 82% of patients receiving aprepitant. Only one study failed to demonstrate a significant effect on complete response rate.27 Aprepitant thereby seems to have a greater impact on emesis than it has on nausea, as was previously reported for conventional chemotherapy.4 One limitation of our study was its focus on short-term toxicities. Influence on hematologic recovery, progression-free survival, or overall survival was not assessed. However, considering the aforementioned trials, a substantial effect seems unlikely.12,23,24 Furthermore, it can be argued that later 5-HT3 antagonists (eg, palonosetron) might have a similar effect, especially in delayed phase.29-31 Still, theresponserateswithoutanNK-1inhibitorsuggestanadditionalbenefit of aprepitant, and results recently published on the combination regimen ofpalonosetron,dexamethasone,andaprepitantinpatientswithmultiple
Percentage of Patients
100
Aprepitant Placebo
97% 90%
80
60
60%
58%
46%
40
41%
Aprepitant Arm
No nausea within 120 hours, % OR No major nausea within 120 hours (VAS ⬎ 25 mm), % OR No emesis within 120 hours, % OR Average time to next episode of emesis, days RR FLIE score Mean SD No impact on daily life (FLIE score ⱖ 108), %
Placebo Arm
P
78
.106
88
.026
65
.0036
85 1.55 94 2.37 78 1.99 7.4
4.8
⬍ .001
0.65 ⬍ .001 114 18
106 26
74
59
.004
Abbreviations: FLIE, Functional Living Index–Emesis; OR, odds ratio; RR, relative rate; SD, standard deviation; VAS, visual analog scale.
myeloma undergoing high-dose melphalan conditioning do not seem superior to our results, although patient numbers were small.25,26,28 Control of delayed CINV remains a major problem. Dexamethasone is effective in preventing delayed CINV; therefore, a higher dose than used in our trial might increase response rates. However, there is general caution, because this could affect rates of infection after ASCT. Olanzapine, an atypical antipsychotic, has shown promising efficacy in this setting.32 Mizukami et al33 reported on increased CINV control rates, adding olanzapine to a standard triple prophylactic regimen in highly and moderately emetogenic chemotherapy. Thus, a further prophylactic drug might help to reduce the high rates of residual vomiting with the currently available agents. Furthermore, a subgroup-specific approach can be considered to reduce potential adverse effects and costs. Important individual risk factors for CINV include sex and previous CINV.34-36 A posthoc subgroup analysis of our trial suggests that men without previous CINV experienced only a marginal benefit from the addition of aprepitant (data not shown). However, our trial was not adequately powered to prove statistical significance of the interaction terms sex, previous CINV, and treatment arm. This finding will have to be corroborated in future studies. The prophylactic combination regimen of granisetron, dexamethasone, and aprepitant proved to be safe and improve quality of life and significantly reduced CINV in our trial. To our knowledge, it is the largest randomized trial with a homogenous patient population, adding prospective data to the current literature. For patients undergoing high-dose melphalan conditioning, addition of aprepitant to a standard antiemetic regimen should be strongly considered.
20
0 Overall Phase (P = .0042)
Acute Phase (P = .022)
Delayed Phase (P = .011)
Fig 2. Patients with complete response in overall, acute, and delayed phases (primary end point, intention-to-treat population). www.jco.org
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under © 2014 by American Society of Clinical Oncology
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3417
3418
© 2014 by American Society of Clinical Oncology
Retrospective with historic control group Retrospective with historic control group
Retrospective with historic controlⴱ
Retrospective with historic controlⴱ
Prospective, nonrandomized
Prospective, nonrandomized
Uchida et al23
Pielichowski et al25
Pielichowski et al26
Paul et al27
Deauna-Limayo et al28
20 (10 with MM)
42
APR, 20; historic control, 40
96
APR, 46; historic control, 42
APR, 26; historic control, 22
MM, lymphoma
MM, NHL, HL, MDS, AML
NA
NHL, HL
AML, ALL, NHL, MDS, other
MM, NHL, HL, leukemia
MM, solid tumors
NA
Placebo, 15; APR, 15
64 (21 with MM)
NHL, AML, MM, ALL, CML, HL, other
Disease
Placebo, 89; APR, 90
No. of Patients
AutoTPX
AutoTPX, alloTPX
AlloTPX
AutoTPX
AlloTPX, BM, CB, PBSCs
AutoTPX, PBSCs
AutoTPX, PBSCs
AlloTPX, autoTPX, BM, CB, PBSCs AlloTPX, autoTPX, BM, PBSCs
TPX and StemCell Source
R-BEAM, melphalan, Bu/Cy, TBI/ Cy, other Melphalan, BEAM
Bu/Cy
MCEC/R, melphalan/ Vel, LEED TBI/Cy, Bu/Cy, Flu/Bu/TBI, Flu/Cy, Flu/ melphalan/ TBI BEAM
Melphalan, T-ICE
TBI/Cy, Bu/Cy, TBI/VP/Cy, BCV TBI/Cy, Bu/Cy
Conditioning Regimen
No emesis, no rescue medication, and NVS ⬍ 2.5
None to two episodes of emesis and no to moderate nausea No to two episodes of emesis and no to moderate nausea No emesis with no to mild nausea and no rescue medication
No emesis with only mild nausea
No emesis with only mild to moderate nausea
No emesis with only mild to moderate nausea, one to two episodes of emesis on day 1 No vomiting and no use of rescue medication
No emesis with only mild to moderate nausea
Definition of Response
DEX/PAL/APR
DEX/PAL/APR v DEX/PAL or DEX/GRAN DEX/PAL/APR v DEX/PAL or DEX/GRAN DEX/OND/APR or DEX/DOL/ APR
GRAN/APR v GRAN
GRAN/APR v GRAN
DEX/GRAN/APR
DEX/OND/APR v DEX/OND/P
DEX/OND/APR v DEX/OND/P
Study Medication
Acute phase, 56% (MM) and 100% (lymphoma); delayed phase, 22% (MM) and 44% (lymphoma); extended phase, 11% (MM) and 22% (lymphoma)
54%
55% v 30% v 20%
82% v 70% v 35%
48% v 24%; P ⫽ .019
Melphalan, 63%; overall, 52%; acute phase, 91%; delayed phase, 52% 42% v 5%; P ⫽ .003
93% v 47%; P ⫽ .014
82% v 66%; P ⬍ .001
Response Rate
Abbreviations: ALL, acute lymphoblastic leukemia; allo, allogeneic; AML, acute myeloid leukemia; APR, aprepitant; auto, autologous; BCV, carmustine, cyclophosphamide, and etoposide; BEAM, carmustine, etoposide, cytarabine, and melphalan; BM, bone marrow; Bu, busulfan; CB, cord blood; CINV, chemotherapy-induced nausea and vomiting; CML, chronic myeloid leukemia; Cy, cyclophosphamide; DEX, dexamethasone; DOL, dolasetron; Flu, fludarabine; GRAN, granisetron; HL, Hodgkin lymphoma; LEED, etoposide, cyclophosphamide, melphalan, and dexamethasone; MCEC/R, ranimustine, carboplatin, etoposide, cyclophosphamide, and rituximab; MDS, myelodysplastic syndrome; MM, multiple myeloma; NA, not available; NHL, non-Hodgkin lymphoma; NVS, nausea visual score; OND, ondansetron; PAL, palonosetron; PBSC, peripheral blood stem cell; R, rituximab; TBI, total-body irradiation; T-ICE, paclitaxel, carboplatin, etoposide, and ifosfamide; TPX, transplantation; Vel, bortezomib; VP, etoposide. ⴱ Study design not explicitly described in manuscript.
Uchida et al24
Prospective, nonrandomized
Prospective, randomized, double blind Prospective, randomized, double blind
Design
Jordan et al22
Bubalo et al20,21
Stiff et al
12
Trial
Table 4. Previously Reported Trials on Prevention of CINV in Hematopoetic Stem-Cell Transplantation With APR
Schmitt et al
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EMNA Study
consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Hartmut Goldschmidt, Janssen Pharmaceuticals (C), Celgene (C), Novartis (C), Onyx Pharmaceuticals (C), Millennium Pharmaceuticals (C); Markus Thalheimer, Merck Sharp & Dohme (C); Gerlinde Egerer, Merck Sharp & Dohme (C) Stock Ownership: None Honoraria: Hartmut Goldschmidt, Janssen Pharmaceuticals, Celgene, Novartis, Chugai Pharmaceutical, Onyx Pharmaceuticals, Millennium Pharmaceuticals; Markus Thalheimer, Merck Sharp & Dohme; Gerd Mikus, Merck Sharp & Dohme; Ju¨rgen Burhenne, Merck Sharp & Dohme; Gerlinde Egerer, Merck Sharp & Dohme Research Funding: Hartmut Goldschmidt, Janssen Pharmaceuticals, Celgene, Novartis, Chugai Pharmaceutical; Ju¨rgen Burhenne, Merck Sharp & Dohme;
REFERENCES 1. Lindley CM, Hirsch JD, O’Neill CV, et al: Quality of life consequences of chemotherapy-induced emesis. Qual Life Res 1:331-340, 1992 2. Roila F, Herrstedt J, Aapro M, et al: Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: Results of the Perugia consensus conference. Ann Oncol 21:v232-v243, 2010 (suppl 5) 3. Basch E, Prestrud AA, Hesketh PJ, et al: Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 29: 4189-4198, 2011 4. 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 highdose cisplatin—The Aprepitant Protocol 052 Study Group. J Clin Oncol 21:4112-4119, 2003 5. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al: Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol 17:1000-1006, 2006 6. Warr DG, Hesketh PJ, Gralla RJ, et al: Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23:2822-2830, 2005 7. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, 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, doubleblind, placebo-controlled trial in Latin America. Cancer 97:3090-3098, 2003 8. Fassas AB, Spencer T, Desikan R, et al: Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients. Br J Haematol 119:164-168, 2002 9. Goldschmidt H, Sonneveld P, Cremer FW, et al: Joint HOVON-50/GMMG-HD3 randomized trial on the effect of thalidomide as part of a high-dose therapy regimen and as maintenance treatment for newly diagnosed myeloma patients. Ann Hematol 82:654-659, 2003 www.jco.org
Gerlinde Egerer, Merck Sharp & Dohme Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: Thomas Schmitt, Merck Sharp & Dohme
AUTHOR CONTRIBUTIONS Conception and design: Thomas Schmitt, Hartmut Goldschmidt, Kai Neben, Anja Freiberger, Johannes Hu¨sing, Markus Thalheimer, Le Hang Pelzl, Gerd Mikus, Anthony D. Ho, Gerlinde Egerer Collection and assembly of data: Thomas Schmitt, Hartmut Goldschmidt, Kai Neben, Anja Freiberger, Martina Gronkowski, Gerd Mikus, Ju¨rgen Burhenne, Anthony D. Ho, Gerlinde Egerer Data analysis and interpretation: Thomas Schmitt, Johannes Hu¨sing, Gerd Mikus, Jur¨gen Burhenne, Anthony D. Ho, Gerlinde Egerer Manuscript writing: All authors Final approval of manuscript: All authors
10. McElwain TJ, Hedley DW, Gordon MY, et al: High dose melphalan and non-cryopreserved autologous bone marrow treatment of malignant melanoma and neuroblastoma. Exp Hematol 7:360-371, 1979 (suppl 5) 11. Selby PJ, McElwain TJ, Nandi AC, et al: Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol 66:55-62, 1987 12. Stiff PJ, Fox-Geiman MP, Kiley K, et al: Prevention of nausea and vomiting associated with stem cell transplant: Results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow Transplant 19:49.e1-55.e1, 2013 13. Martin AR, Pearson JD, Cai B, et al: Assessing the impact of chemotherapy-induced nausea and vomiting on patients’ daily lives: A modified version of the Functional Living Index-Emesis (FLIE) with 5-day recall. Support Care Cancer 11:522-527, 2003 14. Schulz KF, Altman DG, Moher D: CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. PLoS Med 7:e1000251, 2010 15. Gralla RJ, Navari RM, Hesketh PJ, et al: Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Clin Oncol 16:1568-1573, 1998 16. Noble A, Bremer K, Goedhals L, et al: A double-blind, randomised, crossover comparison of granisetron and ondansetron in 5-day fractionated chemotherapy: Assessment of efficacy, safety and patient preference—The Granisetron Study Group. Eur J Cancer 30A:1083-1088, 1994 17. Ondansetron plus dexamethasone versus metoclopramide plus dexamethasone plus diphenhydramine in cisplatin-treated patients with ovarian cancer: Italian Group for Antiemetic Research. Support Care Cancer 2:167-170, 1994 18. Schemper M: Cox analysis of survival data with non-proportional hazard functions. J R Stat Soc 41:455-465, 1992 19. Egerer G, Eisenlohr K, Gronkowski M, et al: The NK receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Br J Clin Pharmacol 70:903-907, 2010 20. Bubalo JS, Leis JF, Curtin PT, et al: A randomized, double-blinded, pilot trial of aprepitant added to standard antiemetics during conditioning therapy for hematopoietic stem cell transplant (HSCT). J Clin Oncol 25, 2007 (suppl; abstr 9112)
21. Bubalo JS, Cherala G, McCune JS, et al: Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J Clin Pharmacol 52:586-594, 2012 22. Jordan K, Jahn F, Jahn P, et al: The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (high-dose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): Efficacy and safety of a triple antiemetic combination. Bone Marrow Transplant 46:784-789, 2011 23. Uchida M, Ikesue H, Miyamoto T, et al: Effectiveness and safety of antiemetic aprepitant in Japanese patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation. Biol Pharm Bull 36:819-824, 2013 24. Uchida M, Kato K, Ikesue H, et al: Efficacy and safety of aprepitant in allogeneic hematopoietic stem cell transplantation. Pharmacotherapy 33:893901, 2013 25. Pielichowski W, Barzal J, Gawronski K, et al: A triple-drug combination to prevent nausea and vomiting following BEAM chemotherapy before autologous hematopoietic stem cell transplantation. Transplant Proc 43:3107-3110, 2011 26. Pielichowski W, Gawronski K, Mlot B, et al: Triple drug combination in the prevention of nausea and vomiting following busulfan plus cyclophosphamide chemotherapy before allogeneic hematopoietic stem cell transplantation. J BUON 16:541-546, 2011 27. Paul B, Trovato JA, Thompson J, et al: Efficacy of aprepitant in patients receiving high-dose chemotherapy with hematopoietic stem cell support. J Oncol Pharm Pract 16:45-51, 2010 28. Deauna-Limayo D, Aljitawi OS, Ganguly S, et al: Combined use of multiday palonosetron with aprepitant and low-dose dexamethasone in prevention of nausea and emesis among patients with multiple myeloma and lymphoma undergoing autologous hematopoietic stem cell transplant: A pilot study. J Oncol Pharm Pract 20:263-269, 2013 29. Murakami M, Hashimoto H, Yamaguchi K, et al: Effectiveness of palonosetron for preventing delayed chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy in patients with gastrointestinal cancer. Support Care Cancer 22:905-909, 2014 30. Schwartzberg L, Barbour SY, Morrow GR, et al: Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and
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granisetron in the prevention of chemotherapyinduced nausea and vomiting (CINV). Support Care Cancer 22:469-477, 2014 31. Celio L, Agustoni F, Ricchini F, et al: Palonosetron plus dexamethasone in highly emetogenic chemotherapy: Pooled data from two phase III trials. Future Oncol 9:1451-1458, 2013 32. Navari RM, Gray SE, Kerr AC: Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A randomized phase III trial. J Support Oncol 9:188-195, 2011
33. Mizukami N, Yamauchi M, Koike K, et al: Olanzapine for the prevention of chemotherapyinduced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: A randomized, double-blind, placebo-controlled study. J Pain Symptom Manage 47:542-550, 2014 34. Sekine I, Segawa Y, Kubota K, et al: Risk factors of chemotherapy-induced nausea and vomiting: Index for personalized antiemetic prophylaxis. Cancer Sci 104:711-717, 2013
35. Molassiotis A, Aapro M, Dicato M, et al: Evaluation of risk factors predicting chemotherapyrelated nausea and vomiting: Results from a European prospective observational study. J Pain Symptom Manage 47:839.e4-848.e4, 2014 36. Hesketh PJ, Grunberg SM, Herrstedt J, et al: Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: Effect of gender on treatment response. Support Care Cancer 14:354-360, 2006
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Acknowledgment We thank Jo¨rn Schu¨ler-Wenigmann for proofreading the manuscript.
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Aprepitant, Granisetron, and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting After High-Dose Melphalan in Autologous Transplantation for Multiple Myeloma: Results of a Randomized, Placebo-Controlled Phase III Trial Thomas Schmitt, Hartmut Goldschmidt, Kai Neben, Anja Freiberger, Johannes Hu¨sing, Martina Gronkowski, Markus Thalheimer, Le Hang Pelzl, Gerd Mikus, Ju¨rgen Burhenne, Anthony D. Ho, and Gerlinde Egerer Thomas Schmitt, Hartmut Goldschmidt, Anja Freiberger, Johannes Hu¨sing, Martina Gronkowski, Markus Thalheimer, Le Hang Pelzl, Gerd Mikus, Ju¨rgen Burhenne, Anthony D. Ho, and Gerlinde Egerer, Heidelberg University Hospital, Heidelberg; and Kai Neben, Klinikum Mittelbaden, Baden-Baden, Germany. Published online ahead of print at www.jco.org on September 15, 2014. Supported by Merck Sharp & Dohme (Germany). Presented at the 49th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 4, 2013. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00571168. Corresponding author: Thomas Schmitt, MD, Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; e-mail: [email protected]. © 2014 by American Society of Clinical Oncology
A
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Purpose The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial. Patients and Methods Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m2 was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index–Emesis (FLIE) questionnaire on days ⫺1 and 6. Results Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P ⫽ .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P ⫽ .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P ⫽ .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (⫾ standard deviation) was 114 ⫾ 18 for aprepitant and 106 ⫾ 26 for placebo (P ⬍ .001). Conclusion The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life. J Clin Oncol 32:3413-3420. © 2014 by American Society of Clinical Oncology
0732-183X/14/3230w-3413w/$20.00 DOI: 10.1200/JCO.2013.55.0095
INTRODUCTION
Nausea and vomiting can severely affect the quality of life of patients receiving chemotherapy and are some of the most dreaded adverse effects.1 Incidence, prevalence, and severity of chemotherapyinduced nausea and vomiting (CINV) are related to several factors, most notably the emetic potential of the chemotherapy itself and patients’ individual risk factors. Because of the implementation of riskadapted prophylaxis and treatment guidelines, incidence of CINV has been reduced substantially.2,3 The most important agents used in clinical
practice today include 5-hydroxytryptamine-3 (5-HT3; serotonin) antagonists, corticosteroids, and neurokinin-1 (NK-1) antagonists. Aprepitant (Emend; Merck, Whitehouse Station, NJ) was the first NK-1 antagonist introduced into clinical care in 2003.4-7 Although classical 5-HT3 antagonists are especially effective in prevention of acute emesis (onset ⬍ 24 hours after chemotherapy administration), NK-1 antagonists and corticosteroids improve control of acute and delayed emesis (onset ⬎ 24 hours after chemotherapy administration). Effect of NK-1 antagonists is pronounced in delayed phase. © 2014 by American Society of Clinical Oncology
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In patients with multiple myeloma age ⬍ 70 years, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care.8,9 Although melphalan, the conditioning agent commonly used in this setting, is generally regarded as only moderately emetogenic, CINV can be significant and distressing. Historic reports before use of 5-HT3 antagonists note almost universal emesis.10,11 Overall, data on the optimal strategy for prevention of CINV in ASCT are scarce, and current American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer (MASCC) guidelines recommend the combination of dexamethasone and a 5-HT3 antagonist.2,3 An NK-1 antagonist can be considered, although data supporting its use are limited, because larger prospective trials are missing and/or combine heterogeneous patient populations, conditioning regimens, and autologous as well as allogeneic transplantations.12 Here we report the results of a prospective, randomized, placebo-controlled trial of aprepitant, granisetron, and dexamethasone in patients with multiple myeloma undergoing high-dose melphalan conditioning. PATIENTS AND METHODS Trial Design This protocol was designed as a prospective, placebo-controlled, randomized, double-blind, parallel-group, single-center study conducted at the Heidelberg University Hospital (Heidelberg, Germany). Currently, we perform approximately 200 autologous transplantations at our center per year, making it the largest program in Germany. Written informed consent was obtained from all patients before trial participation. A computer-generated randomization list (SAS PLAN; SAS Institute, Cary, NC) was used to allocate treatment codes on a one-to-one basis for the two treatment arms. This task was conducted at the Coordination Centre for Clinical Trials (KKS; Heidelberg, Germany) independent of all other trial procedures. The trial was carried out according to good clinical practice and the principles stated in the Declaration of Helsinki in 1964, as well as all subsequent revisions. The study protocol was approved by the institutional ethics committee and the competent authority (Bundesinstitut fu¨r Arzneimittel und Medizinprodukte, Bonn, Germany; EudraCT-No. 2004004956-38). Inclusion and Exclusion Criteria All patients (age ⱖ 18 years) with multiple myeloma undergoing autologous transplantation after high-dose melphalan conditioning were eligible for participation. Exclusion criteria were as follows: nausea or vomiting within 12 hours before planned high-dose chemotherapy, any antiemetic treatment within 24 hours before planned high-dose chemotherapy, intake of corticosteroids, and known hypersensitivity to the investigational product. All enrolled patients received a randomization number identifying him or her throughout the course of the trial. Study Treatment Trial duration for each individual patient included a treatment phase of 4 days (days 1 to 4) and follow-up phase of 3 days (days 5 to 7). Patients were randomly assigned at a one-to-one ratio to receive either aprepitant 125 mg orally on day 1 and 80 mg orally on days 2 to 4, granisetron 2 mg orally on days 1 to 4, and dexamethasone 4 mg orally on day 1 and 2 mg orally on days 2 to 3 or matching placebo orally on days 1 to 4, granisetron 2 mg orally on days 1 to 4, and dexamethasone 8 mg orally on day 1 and 4 mg orally on days 2 to 3 (Table 1). To reduce the risk of infection after ASCT, a lower dose of dexamethasone than generally recommended for highly emetogenic regimens was chosen. Furthermore, according to the summary of product characteristics of aprepitant, the dose of dexametha3414
© 2014 by American Society of Clinical Oncology
Table 1. Treatment Schedule Melphalan 100 mg/m2 (day) Regimen Arm A Aprepitant, mg Granisetron, mg Dexamethasone, mg Arm B Placebo, mg Granisetron, mg Dexamethasone, mg
ASCT (day)
1
2
3
4
125 2 4
80 2 2
80 2 2
80 2
125 2 8
80 2 4
80 2 4
80 2
Abbreviation: ASCT, autologous stem-cell transplantation.
sone was reduced by 50% when coadministered. Study medication was manufactured, labeled, and packed by the pharmacy department of the Heidelberg University Hospital according to the randomization list. Appearance and dosage of aprepitant, placebo, and dexamethasone were double blinded in both treatment arms. Aprepitant/placebo and granisetron/dexamethasone were administered 60 and 30 minutes before administration of melphalan (100 mg/m2 intravenously on days 1 to 2), respectively. Rescue medication for breakthrough CINV was left up to the treating physician. Study End Points The primary end point of this study was overall complete response, defined as no emesis and no rescue therapy within 120 hours of melphalan administration. The time interval of 120 hours was chosen because it can be assumed that additional cofactors (eg, mucositis and antibiotic use) influence rates of nausea and vomiting after this point in time. Preplanned secondary end points included complete response, defined as no emesis and no rescue therapy in acute (0 to 24 hours) or delayed phase (25 to 120 hours), rates of emesis, nausea and significant nausea, number of adverse events, and impact on quality of daily life, as assessed by modified Functional Living Index–Emesis (FLIE) score. Assessment Patients were asked to complete a diary on a daily basis recording episodes of vomiting (vomits and/or dry heaves) and presence or absence of nausea and its severity on a 100-mm visual analog scale (VAS). No nausea was defined as VAS ⬍ 5 mm and significant nausea as VAS ⬎ 25 mm. Furthermore, rescue therapy was recorded over a period of 5 days. A FLIE questionnaire with a 5-day recall was completed on day ⫺1 for baseline assessment and training and on the morning of day 6.13 No impact on daily life was defined as an average FLIE item score ⬎ 6 on the 7-point scale (or respectively, total score ⱖ 108). Adverse events were recorded on days 1 to 7, and safety laboratory evaluations (CBC and coagulation, renal, and liver function tests) were performed during screening and on days 4 and 7. Adverse events were recorded according to Common Terminology Criteria for Adverse Events (version 3.0) and further graded by the principal investigator as mild (temporary event well tolerated by patient), moderate (event resulting in discomfort for patient and impairing normal daily activity), or severe (event resulting in substantial impairment of normal daily activity). Statistical Analyses The necessary study sample size (N ⫽ 362) was calculated with respect to a 2 test of the primary end point, the proportion of overall complete response. The test was carried out for the two-sided null hypothesis of no difference in proportion. A difference in proportion of at least 15% (65% v 50%) was determined to cause a significant effect (at .05 level), with a power of 0.80. A preplanned interim analysis was performed after the inclusion of 180 patients at a level of .01, and the final analysis was JOURNAL OF CLINICAL ONCOLOGY
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performed after 362 patients at a level of .04, maintaining an overall level of .05. Efficacy end points were analyzed following a strict intention-to-treat (ITT) approach, as recommended in International Conference on Harmonisation E9 guidelines. All analyses of the primary end point were based on logistic regression models, including the impact of previous CINV and sex as explanatory variables. Rates of emesis were modeled using a timeto-event model allowing multiple events per patient, following the Andersen-Gill multiplicative hazards model. Assumptions of proportionality over time for treatment covariates were checked. To give an idea about the extent of emesis, mean waiting time to next emesis event was roughly estimated by dividing total time patients were observed by number of events in each group. Treatments were compared with respect to all other dichotomous variables using 2 tests and uncorrected CIs, and effects were presented as odds ratios (ORs). Difference in FLIE score between treatment arms was assessed by t test. No advanced algorithm to replace missing values was applied, because there was a high level of completeness. All analyses were prespecified in a statistical analysis plan, which was completed before the database was unblinded. Only the primary analysis was controlled for type I error; therefore, analyses of secondary parameters should be viewed as exploratory. The plan was updated after interim analysis, but the updates did not affect any procedures performed in the interim analysis. J.H. (KKS) performed all statistical analyses. For data management and statistical testing, SAS software (version 9.3) was used.
RESULTS
Between July 2005 and January 2012, a total of 609 patients with multiple myeloma undergoing high-dose melphalan therapy and ASCT were screened, and 363 were randomly assigned. Four patients underwent double ASCT and were excluded from participating twice. One patient was randomly assigned but found to have plasma cell leukemia before receiving study medication and was therefore excluded from the efficacy analysis. Therefore, 181 patients were randomly assigned to aprepitant and 181 to placebo and were available for ITT analysis. Overall, 36 and 46 patients in the treatment and placebo arms, respectively, were excluded from per-protocol (PP) analysis for not meeting eligibility criteria, not receiving melphalan within the required timeframe after intake of study medication, receiving additional antiemetic medication, and/or having problems with the FLIE questionnaire. The PP set thus comprised 145 and 135 patients in the aprepitant and placebo arms, respectively. A CONSORT diagram is shown in Figure 1.14 All patients completed at least 96 of 120 hours postrandomization. Sex and age distributions were well balanced between both arms. In three patient cases, no information on prior CINV was obtained; these were treated as if there had been none. Patient characteristics are summarized in Table 2. Efficacy Analyses An interim analysis for the primary end point was performed after inclusion of 180 patients. Statistical testing failed to prove a difference between the two treatment arms at a significance level of .01 (OR, 1.60; P ⫽ .15). Therefore, the study was continued until accrual of 362 patients. In the ITT population, significantly more patients receiving aprepitant reported no emesis and no additional antiemetic treatment within 120 hours of melphalan administration (overall complete response) compared with placebo (58% v 41%; OR, 1.92; 95% CI, 1.23 to 3.00; P ⫽ .0042). As expected, the overall effect was more pronounced in the PP analysis (59% v 39%; OR, 2.16; 95% CI, 1.30 to 3.60; P ⫽ .003). www.jco.org
No emesis or additional antiemetic treatment in the acute phase (⬍ 24 hours after melphalan administration) was reported by 97% and 90% of patients receiving aprepitant and placebo, respectively (OR, 3.11; 95% CI, 1.23 to 8.92; P ⫽ .022). During the delayed phase (24 to 120 hours after melphalan administration), this was achieved in 60% and 46% of patients, respectively (OR, 1.80; 95% CI, 1.15 to 2.85; P ⫽ .011), suggesting a lasting benefit after 24 hours (Fig 2). Major nausea was prevented in 94% and 88% of patients in the aprepitant and placebo arms, respectively (OR, 2.37; 95% CI, 1.09 to 5.15; P ⫽ .026). Effect on overall nausea (85% v 78%; OR, 1.55; 95% CI, 0.91 to 2.65; P ⫽ .106) was less pronounced. Absence of emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P ⫽ .0036) within 120 hours of melphalan administration was increased for patients receiving aprepitant. Mean time to next episode of emesis was prolonged from 4.8 (placebo) to 7.4 days (aprepitant), with a resulting relative rate of 0.65 (95% CI, 0.50 to 0.83; P ⬍ .001). Effect on necessity for rescue medication for the entire study period of 7 days was less salient (48% v 40%; OR, 1.34; 95% CI, 0.88 to 2.03; P ⫽ .169). Analysis of quality of life was based on a complete case approach. A total of 356 patients completed the questionnaire by protocol; 74% of those receiving aprepitant, compared with 59% of patients receiving placebo, had an FLIE score indicating no impact on daily life (P ⫽ .004). Mean total FLIE score (⫾ standard deviation) was 114 ⫾ 18 for those receiving aprepitant and 106 ⫾ 26 points for those receiving placebo (P ⬍ .001). Efficacy data are summarized in Table 3. Safety Analysis Rates of adverse events did not significantly differ between the two treatment arms. Intensity of the reported adverse events was mild (64% v 64%), moderate (32% v 34%), and severe (3% v 3%) for aprepitant and placebo, respectively. The most frequently observed adverse events (aprepitant v placebo) were leukopenia (mild, 10% v 10%; moderate, 49% v 51%; severe, 18% v 15%), hypocalcemia (mild, 45% v 46%; moderate, 3% v 2%), fatigue (mild, 34% v 29%; moderate, 27% v 29%), edema (mild, 41% v 38%; moderate, 8% v 8%), and constipation (mild, 25% v 28%; moderate, 10% v 9%). Six patients terminated the study prematurely (two in aprepitant arm; four in placebo arm); reasons were lack of compliance (placebo, n ⫽ 2), uncontrollable emesis (placebo, n ⫽ 1), seizure (aprepitant, n ⫽ 1), and short-term change of conditioning regimen (placebo, n ⫽ 1). One patient in the aprepitant arm died during study participation, most likely as a result of dimethyl sulfoxide (DSMO) –induced encephalopathy. DMSO is an agent used for cryopreservation of hematopoetic stem cells at our center. Cause of death was considered unrelated to study medication. DISCUSSION
Nausea and vomiting are some of the most distressing adverse effects for patients undergoing chemotherapy. However, the optimal prophylactic regimen for patients receiving high-dose chemotherapy and ASCT is still unknown, and available data are limited. Current ASCO and ESMO/MASCC guidelines recommend the combination of a 5-HT3 antagonist and dexamethasone.2,3 With © 2014 by American Society of Clinical Oncology
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Screened (N = 609)
Excluded (n = 246) Participation (n = 131) declined High-dose therapy (n = 30) other than melphalan Contraindications (n = 59) Previous participation (n = 4) in same trial Participation in (n = 12) other trial Other reasons (n = 10)
Randomly assigned (n = 363)
Aprepitant (n = 182)
Placebo (n = 181)
Did not receive study medication (n = 1)
Did not receive study medication (n = 0) Full analysis set (n = 181)
Excluded from perprotocol analysis Eligibility criteria violated Administration of melphalan outside time frame Completion of FLIE not by patient
Full analysis set (n = 181) Excluded from perprotocol analysis Eligibility criteria violated Additional antiemetics Administration of melphalan outside time frame Completion of FLIE not by patient Delayed completion of FLIE
(n = 36)* (n = 4) (n = 33)
(n = 4)
Per-protocol set (n = 145)
(n = 46)* (n = 2) (n = 1) (n = 40)
(n = 2) (n = 2)
Per-protocol set (n = 135)
Fig 1. CONSORT diagram. FLIE, Functional Living Index–Emesis. (*) Multiple reasons for exclusion per patient may apply.
this standard prophylactic regimen, it can be hypothesized that 70% to 80% of patients have effective control of acute CINV.15-17 However, a majority of patients will experience delayed CINV. Here we report the results of our phase IIIb trial of granisetron, dexamethasone, and aprepitant for patients with multiple myeloma undergoing high-dose melphalan conditioning and ASCT. To our knowledge, this is the largest prospective, randomized phase III trial assessing this question. The combination regimen resulted in a significant reduction of major nausea and emesis. In the ITT population, no emesis and no antiemetic rescue medication within 120 hours of melphalan administration (overall phase) were reported for 58% and 41% of patients receiving aprepitant and placebo, respectively (OR, 1.92; 95% CI, 1.23 to 3.00; P ⫽ .0042); the effect in the PP set was slightly pronounced 3416
© 2014 by American Society of Clinical Oncology
(59% v 39%; OR, 2.16; 95% CI, 1.30 to 3.60; P ⫽ .003). The majority of patients excluded from the PP analysis did not receive the melphalan infusion within the required timeframe after intake of study medication. Thus, it can be speculated that suboptimal drug plasma levels at least influenced rates of acute CINV. However, the overall effect seemed to be negligible. Tests regarding proportionality of hazards revealed that treatment effects converged with time. This could have led to underestimation of treatment effect, but we opted against diverging from the analysis plan with respect to the primary end point.18 Rates of adverse events between the treatment arms did not differ, and melphalan pharmacokinetics were not altered by concomitant aprepitant administration (results reported elsewhere).19 Quality of life as assessed by FLIE questionnaire was improved significantly. JOURNAL OF CLINICAL ONCOLOGY
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Table 3. Efficacy Data: Secondary End Points
Table 2. Patient Demographic and Clinical Characteristics Aprepitant Arm Characteristic Sex Male Female Age, years Median Range Previous CINV None Light Moderate Severe Not available
Efficacy End Point Placebo Arm
All Patients
No.
%
No.
%
No.
%
120 61
66 34
110 71
61 39
230 132
64 36
58.3 27-72 100 41 32 6 2
57.9 35-72 55 23 18 3 1
85 47 28 19 2
58.1
47 26 15 11 1
185 88 60 25 4
51 24 17 7 1
Abbreviation: CINV, chemotherapy-induced nausea and vomiting.
Direct comparison of our results with literature is complicated by different definitions of the primary end point, the mostly retrospective character of the published results, and the diversity of disease-specific conditioning regimens with varying emetic potential (Table 4). The largest prospective trial so far was reported by Stiff et al,12 showing no emesis with no or only mild nausea in 82% of patients receiving aprepitant. Only one study failed to demonstrate a significant effect on complete response rate.27 Aprepitant thereby seems to have a greater impact on emesis than it has on nausea, as was previously reported for conventional chemotherapy.4 One limitation of our study was its focus on short-term toxicities. Influence on hematologic recovery, progression-free survival, or overall survival was not assessed. However, considering the aforementioned trials, a substantial effect seems unlikely.12,23,24 Furthermore, it can be argued that later 5-HT3 antagonists (eg, palonosetron) might have a similar effect, especially in delayed phase.29-31 Still, theresponserateswithoutanNK-1inhibitorsuggestanadditionalbenefit of aprepitant, and results recently published on the combination regimen ofpalonosetron,dexamethasone,andaprepitantinpatientswithmultiple
Percentage of Patients
100
Aprepitant Placebo
97% 90%
80
60
60%
58%
46%
40
41%
Aprepitant Arm
No nausea within 120 hours, % OR No major nausea within 120 hours (VAS ⬎ 25 mm), % OR No emesis within 120 hours, % OR Average time to next episode of emesis, days RR FLIE score Mean SD No impact on daily life (FLIE score ⱖ 108), %
Placebo Arm
P
78
.106
88
.026
65
.0036
85 1.55 94 2.37 78 1.99 7.4
4.8
⬍ .001
0.65 ⬍ .001 114 18
106 26
74
59
.004
Abbreviations: FLIE, Functional Living Index–Emesis; OR, odds ratio; RR, relative rate; SD, standard deviation; VAS, visual analog scale.
myeloma undergoing high-dose melphalan conditioning do not seem superior to our results, although patient numbers were small.25,26,28 Control of delayed CINV remains a major problem. Dexamethasone is effective in preventing delayed CINV; therefore, a higher dose than used in our trial might increase response rates. However, there is general caution, because this could affect rates of infection after ASCT. Olanzapine, an atypical antipsychotic, has shown promising efficacy in this setting.32 Mizukami et al33 reported on increased CINV control rates, adding olanzapine to a standard triple prophylactic regimen in highly and moderately emetogenic chemotherapy. Thus, a further prophylactic drug might help to reduce the high rates of residual vomiting with the currently available agents. Furthermore, a subgroup-specific approach can be considered to reduce potential adverse effects and costs. Important individual risk factors for CINV include sex and previous CINV.34-36 A posthoc subgroup analysis of our trial suggests that men without previous CINV experienced only a marginal benefit from the addition of aprepitant (data not shown). However, our trial was not adequately powered to prove statistical significance of the interaction terms sex, previous CINV, and treatment arm. This finding will have to be corroborated in future studies. The prophylactic combination regimen of granisetron, dexamethasone, and aprepitant proved to be safe and improve quality of life and significantly reduced CINV in our trial. To our knowledge, it is the largest randomized trial with a homogenous patient population, adding prospective data to the current literature. For patients undergoing high-dose melphalan conditioning, addition of aprepitant to a standard antiemetic regimen should be strongly considered.
20
0 Overall Phase (P = .0042)
Acute Phase (P = .022)
Delayed Phase (P = .011)
Fig 2. Patients with complete response in overall, acute, and delayed phases (primary end point, intention-to-treat population). www.jco.org
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under © 2014 by American Society of Clinical Oncology
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Retrospective with historic control group Retrospective with historic control group
Retrospective with historic controlⴱ
Retrospective with historic controlⴱ
Prospective, nonrandomized
Prospective, nonrandomized
Uchida et al23
Pielichowski et al25
Pielichowski et al26
Paul et al27
Deauna-Limayo et al28
20 (10 with MM)
42
APR, 20; historic control, 40
96
APR, 46; historic control, 42
APR, 26; historic control, 22
MM, lymphoma
MM, NHL, HL, MDS, AML
NA
NHL, HL
AML, ALL, NHL, MDS, other
MM, NHL, HL, leukemia
MM, solid tumors
NA
Placebo, 15; APR, 15
64 (21 with MM)
NHL, AML, MM, ALL, CML, HL, other
Disease
Placebo, 89; APR, 90
No. of Patients
AutoTPX
AutoTPX, alloTPX
AlloTPX
AutoTPX
AlloTPX, BM, CB, PBSCs
AutoTPX, PBSCs
AutoTPX, PBSCs
AlloTPX, autoTPX, BM, CB, PBSCs AlloTPX, autoTPX, BM, PBSCs
TPX and StemCell Source
R-BEAM, melphalan, Bu/Cy, TBI/ Cy, other Melphalan, BEAM
Bu/Cy
MCEC/R, melphalan/ Vel, LEED TBI/Cy, Bu/Cy, Flu/Bu/TBI, Flu/Cy, Flu/ melphalan/ TBI BEAM
Melphalan, T-ICE
TBI/Cy, Bu/Cy, TBI/VP/Cy, BCV TBI/Cy, Bu/Cy
Conditioning Regimen
No emesis, no rescue medication, and NVS ⬍ 2.5
None to two episodes of emesis and no to moderate nausea No to two episodes of emesis and no to moderate nausea No emesis with no to mild nausea and no rescue medication
No emesis with only mild nausea
No emesis with only mild to moderate nausea
No emesis with only mild to moderate nausea, one to two episodes of emesis on day 1 No vomiting and no use of rescue medication
No emesis with only mild to moderate nausea
Definition of Response
DEX/PAL/APR
DEX/PAL/APR v DEX/PAL or DEX/GRAN DEX/PAL/APR v DEX/PAL or DEX/GRAN DEX/OND/APR or DEX/DOL/ APR
GRAN/APR v GRAN
GRAN/APR v GRAN
DEX/GRAN/APR
DEX/OND/APR v DEX/OND/P
DEX/OND/APR v DEX/OND/P
Study Medication
Acute phase, 56% (MM) and 100% (lymphoma); delayed phase, 22% (MM) and 44% (lymphoma); extended phase, 11% (MM) and 22% (lymphoma)
54%
55% v 30% v 20%
82% v 70% v 35%
48% v 24%; P ⫽ .019
Melphalan, 63%; overall, 52%; acute phase, 91%; delayed phase, 52% 42% v 5%; P ⫽ .003
93% v 47%; P ⫽ .014
82% v 66%; P ⬍ .001
Response Rate
Abbreviations: ALL, acute lymphoblastic leukemia; allo, allogeneic; AML, acute myeloid leukemia; APR, aprepitant; auto, autologous; BCV, carmustine, cyclophosphamide, and etoposide; BEAM, carmustine, etoposide, cytarabine, and melphalan; BM, bone marrow; Bu, busulfan; CB, cord blood; CINV, chemotherapy-induced nausea and vomiting; CML, chronic myeloid leukemia; Cy, cyclophosphamide; DEX, dexamethasone; DOL, dolasetron; Flu, fludarabine; GRAN, granisetron; HL, Hodgkin lymphoma; LEED, etoposide, cyclophosphamide, melphalan, and dexamethasone; MCEC/R, ranimustine, carboplatin, etoposide, cyclophosphamide, and rituximab; MDS, myelodysplastic syndrome; MM, multiple myeloma; NA, not available; NHL, non-Hodgkin lymphoma; NVS, nausea visual score; OND, ondansetron; PAL, palonosetron; PBSC, peripheral blood stem cell; R, rituximab; TBI, total-body irradiation; T-ICE, paclitaxel, carboplatin, etoposide, and ifosfamide; TPX, transplantation; Vel, bortezomib; VP, etoposide. ⴱ Study design not explicitly described in manuscript.
Uchida et al24
Prospective, nonrandomized
Prospective, randomized, double blind Prospective, randomized, double blind
Design
Jordan et al22
Bubalo et al20,21
Stiff et al
12
Trial
Table 4. Previously Reported Trials on Prevention of CINV in Hematopoetic Stem-Cell Transplantation With APR
Schmitt et al
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consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Hartmut Goldschmidt, Janssen Pharmaceuticals (C), Celgene (C), Novartis (C), Onyx Pharmaceuticals (C), Millennium Pharmaceuticals (C); Markus Thalheimer, Merck Sharp & Dohme (C); Gerlinde Egerer, Merck Sharp & Dohme (C) Stock Ownership: None Honoraria: Hartmut Goldschmidt, Janssen Pharmaceuticals, Celgene, Novartis, Chugai Pharmaceutical, Onyx Pharmaceuticals, Millennium Pharmaceuticals; Markus Thalheimer, Merck Sharp & Dohme; Gerd Mikus, Merck Sharp & Dohme; Ju¨rgen Burhenne, Merck Sharp & Dohme; Gerlinde Egerer, Merck Sharp & Dohme Research Funding: Hartmut Goldschmidt, Janssen Pharmaceuticals, Celgene, Novartis, Chugai Pharmaceutical; Ju¨rgen Burhenne, Merck Sharp & Dohme;
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Gerlinde Egerer, Merck Sharp & Dohme Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: Thomas Schmitt, Merck Sharp & Dohme
AUTHOR CONTRIBUTIONS Conception and design: Thomas Schmitt, Hartmut Goldschmidt, Kai Neben, Anja Freiberger, Johannes Hu¨sing, Markus Thalheimer, Le Hang Pelzl, Gerd Mikus, Anthony D. Ho, Gerlinde Egerer Collection and assembly of data: Thomas Schmitt, Hartmut Goldschmidt, Kai Neben, Anja Freiberger, Martina Gronkowski, Gerd Mikus, Ju¨rgen Burhenne, Anthony D. Ho, Gerlinde Egerer Data analysis and interpretation: Thomas Schmitt, Johannes Hu¨sing, Gerd Mikus, Jur¨gen Burhenne, Anthony D. Ho, Gerlinde Egerer Manuscript writing: All authors Final approval of manuscript: All authors
10. McElwain TJ, Hedley DW, Gordon MY, et al: High dose melphalan and non-cryopreserved autologous bone marrow treatment of malignant melanoma and neuroblastoma. Exp Hematol 7:360-371, 1979 (suppl 5) 11. Selby PJ, McElwain TJ, Nandi AC, et al: Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol 66:55-62, 1987 12. Stiff PJ, Fox-Geiman MP, Kiley K, et al: Prevention of nausea and vomiting associated with stem cell transplant: Results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol Blood Marrow Transplant 19:49.e1-55.e1, 2013 13. Martin AR, Pearson JD, Cai B, et al: Assessing the impact of chemotherapy-induced nausea and vomiting on patients’ daily lives: A modified version of the Functional Living Index-Emesis (FLIE) with 5-day recall. Support Care Cancer 11:522-527, 2003 14. Schulz KF, Altman DG, Moher D: CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. PLoS Med 7:e1000251, 2010 15. Gralla RJ, Navari RM, Hesketh PJ, et al: Single-dose oral granisetron has equivalent antiemetic efficacy to intravenous ondansetron for highly emetogenic cisplatin-based chemotherapy. J Clin Oncol 16:1568-1573, 1998 16. Noble A, Bremer K, Goedhals L, et al: A double-blind, randomised, crossover comparison of granisetron and ondansetron in 5-day fractionated chemotherapy: Assessment of efficacy, safety and patient preference—The Granisetron Study Group. Eur J Cancer 30A:1083-1088, 1994 17. Ondansetron plus dexamethasone versus metoclopramide plus dexamethasone plus diphenhydramine in cisplatin-treated patients with ovarian cancer: Italian Group for Antiemetic Research. Support Care Cancer 2:167-170, 1994 18. Schemper M: Cox analysis of survival data with non-proportional hazard functions. J R Stat Soc 41:455-465, 1992 19. Egerer G, Eisenlohr K, Gronkowski M, et al: The NK receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma. Br J Clin Pharmacol 70:903-907, 2010 20. Bubalo JS, Leis JF, Curtin PT, et al: A randomized, double-blinded, pilot trial of aprepitant added to standard antiemetics during conditioning therapy for hematopoietic stem cell transplant (HSCT). J Clin Oncol 25, 2007 (suppl; abstr 9112)
21. Bubalo JS, Cherala G, McCune JS, et al: Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J Clin Pharmacol 52:586-594, 2012 22. Jordan K, Jahn F, Jahn P, et al: The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (high-dose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): Efficacy and safety of a triple antiemetic combination. Bone Marrow Transplant 46:784-789, 2011 23. Uchida M, Ikesue H, Miyamoto T, et al: Effectiveness and safety of antiemetic aprepitant in Japanese patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation. Biol Pharm Bull 36:819-824, 2013 24. Uchida M, Kato K, Ikesue H, et al: Efficacy and safety of aprepitant in allogeneic hematopoietic stem cell transplantation. Pharmacotherapy 33:893901, 2013 25. Pielichowski W, Barzal J, Gawronski K, et al: A triple-drug combination to prevent nausea and vomiting following BEAM chemotherapy before autologous hematopoietic stem cell transplantation. Transplant Proc 43:3107-3110, 2011 26. Pielichowski W, Gawronski K, Mlot B, et al: Triple drug combination in the prevention of nausea and vomiting following busulfan plus cyclophosphamide chemotherapy before allogeneic hematopoietic stem cell transplantation. J BUON 16:541-546, 2011 27. Paul B, Trovato JA, Thompson J, et al: Efficacy of aprepitant in patients receiving high-dose chemotherapy with hematopoietic stem cell support. J Oncol Pharm Pract 16:45-51, 2010 28. Deauna-Limayo D, Aljitawi OS, Ganguly S, et al: Combined use of multiday palonosetron with aprepitant and low-dose dexamethasone in prevention of nausea and emesis among patients with multiple myeloma and lymphoma undergoing autologous hematopoietic stem cell transplant: A pilot study. J Oncol Pharm Pract 20:263-269, 2013 29. Murakami M, Hashimoto H, Yamaguchi K, et al: Effectiveness of palonosetron for preventing delayed chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy in patients with gastrointestinal cancer. Support Care Cancer 22:905-909, 2014 30. Schwartzberg L, Barbour SY, Morrow GR, et al: Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and
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granisetron in the prevention of chemotherapyinduced nausea and vomiting (CINV). Support Care Cancer 22:469-477, 2014 31. Celio L, Agustoni F, Ricchini F, et al: Palonosetron plus dexamethasone in highly emetogenic chemotherapy: Pooled data from two phase III trials. Future Oncol 9:1451-1458, 2013 32. Navari RM, Gray SE, Kerr AC: Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A randomized phase III trial. J Support Oncol 9:188-195, 2011
33. Mizukami N, Yamauchi M, Koike K, et al: Olanzapine for the prevention of chemotherapyinduced nausea and vomiting in patients receiving highly or moderately emetogenic chemotherapy: A randomized, double-blind, placebo-controlled study. J Pain Symptom Manage 47:542-550, 2014 34. Sekine I, Segawa Y, Kubota K, et al: Risk factors of chemotherapy-induced nausea and vomiting: Index for personalized antiemetic prophylaxis. Cancer Sci 104:711-717, 2013
35. Molassiotis A, Aapro M, Dicato M, et al: Evaluation of risk factors predicting chemotherapyrelated nausea and vomiting: Results from a European prospective observational study. J Pain Symptom Manage 47:839.e4-848.e4, 2014 36. Hesketh PJ, Grunberg SM, Herrstedt J, et al: Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: Effect of gender on treatment response. Support Care Cancer 14:354-360, 2006
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Acknowledgment We thank Jo¨rn Schu¨ler-Wenigmann for proofreading the manuscript.
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