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Phase III Trial of Casopitant, a Novel Neurokinin-1 Receptor Antagonist, for the Prevention of Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy
Abstract
The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC).
Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) –based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.
A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.
Nausea and vomiting are among the most feared side effects of chemotherapy among patients with cancer.1 Several studies have reported an underestimation of chemotherapy-induced nausea and vomiting (CINV) by health care providers, especially of the prevalence of delayed nausea and vomiting.2,3
Failure to prevent CINV can negatively affect patient outcome by contributing to low adherence and withdrawal from potentially effective or curative chemotherapy.4,5 Optimal prevention of CINV in the first cycle of chemotherapy can decrease the likelihood of CINV in subsequent cycles.6 Furthermore, preventing CINV from cycle 1 lowers the probability of anticipatory CINV in subsequent cycles.7
Emesis is an autonomic reflex controlled by multiple neurotransmitter systems; two of the most important systems are the serotonin/5-hydroxytryptamine receptor 3 (5-HT3) and substance P/neurokinin-1 (NK-1) receptor systems.8 Blocking both the 5-HT3 and NK-1 neurotransmitter receptors has been demonstrated to reduce CINV in patients receiving chemotherapy.9–13
When added to an antiemetic regimen of ondansetron and dexamethasone, the novel NK-1 receptor antagonist casopitant demonstrated antiemetic efficacy in a phase II dose-ranging trial in patients receiving moderately emetogenic chemotherapy (MEC). This phase II trial also included a casopitant single oral dose arm, which seemed to provide the same clinical benefit as multiple doses of casopitant to patients receiving MEC.13
On the basis of the phase II study results, a phase III clinical trial was conducted to evaluate selected casopitant regimens in a larger population and to further define the optimal schedule and use in a population receiving MEC, specifically the combination of an anthracycline and cyclophosphamide (AC), which is considered to be among the most emetogenic of the MEC regimens.14 Here we report the findings from the first cycle of chemotherapy.
Patients were included in this trial if they were ≥ 18 years of age, chemotherapy-naïve, and had an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients had to be scheduled to receive one of the following AC-based regimens for the treatment of a solid malignant tumor to be eligible for the trial: cyclophosphamide administered intravenously (IV; 500 to 1,500 mg/m2) and doxorubicin IV (≥ 40 mg/m2) or cyclophosphamide IV (500 to 1,500 mg/m2) and epirubicin IV (≥ 60 mg/m2). Administration of additional chemotherapy was allowed if the additional agent(s) was of low or minimal emetogenic potential. Patients were required to have laboratory values demonstrating adequate hematologic status (absolute neutrophil count ≥ 1,500/μL, platelets ≥ 100,000/μL) and adequate liver function (bilirubin ≤ 1.5× upper limit of normal [ULN], AST/ALT ≤ 2.5× ULN, or in the presence of known liver metastases, AST/ALT ≤ 5.0× ULN). All patients of childbearing potential were required to use birth control.
Patients were ineligible for the trial if they had previously received chemotherapy or an NK-1 receptor antagonist or if they had received any drug with moderate or high emetogenic potential in the 48 hours before receiving the first study drug. They also could not have received an investigational drug in the 30 days before receiving study drugs or medications with known or potential antiemetic activity within the 24 hours before receiving study drug. Patients were ineligible for the trial if they were scheduled to receive taxane therapy during cycle 1 as a result of concomitant administration of corticosteroids. Patients taking the CYP3A4 substrates astemizole, pimozide, terfenadine, repaglinide, or torsemide were excluded, as were patients with known hypersensitivity to dexamethasone or 5-HT3 receptor antagonists. Other exclusion criteria included having received CYP3A4 and CYP3A5 inducers within 14 days or strong or moderate CYP3A4/CYP3A5 inhibitors 2 days before the first dose of drug. Pregnant or lactating patients were excluded from the trial.
This randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 196 centers in 32 countries. After the initial screening visit, investigators used a Randomization and Medication system to register patients for the trial, stratify patients by sex, and randomly assign patients into one of the following study arms: control, casopitant single oral dose, casopitant 3-day oral dosage, or casopitant 3-day IV/oral dosage (Table 1).
|
| Group | Day 1 | Day 2 | Day 3 |
|---|---|---|---|
| 1 | Casopitant placebo oral | Casopitant placebo oral | Casopitant placebo oral |
| Casopitant placebo IV | Ondansetron 8 mg oral twice daily | Ondansetron 8 mg oral twice daily | |
| Ondansetron 8 mg oral twice daily | |||
| Dexamethasone 8 mg IV | |||
| 2 | Casopitant 150 mg oral | Casopitant placebo oral | Casopitant placebo oral |
| Casopitant placebo IV | Ondansetron 8 mg oral twice daily | Ondansetron 8 mg oral twice daily | |
| Ondansetron 8 mg oral twice daily | |||
| Dexamethasone 8 mg IV | |||
| 3 | Casopitant 150 mg oral | Casopitant 50 mg oral | Casopitant 50 mg oral |
| Casopitant placebo IV | Ondansetron 8 mg oral twice daily | Ondansetron 8 mg oral twice daily | |
| Ondansetron 8 mg oral twice daily | |||
| Dexamethasone 8 mg IV | |||
| 4 | Casopitant placebo oral | Casopitant 50 mg oral | Casopitant 50 mg oral |
| Casopitant 90 mg IV | Ondansetron 8 mg oral twice daily | Ondansetron 8 mg oral twice daily | |
| Ondansetron 8 mg oral twice daily | |||
| Dexamethasone 8 mg IV |
Abbreviation: IV, intravenous.
All patients in the trial, regardless of study arm assignment, received dexamethasone 8 mg IV on day 1 and ondansetron 8 mg orally (PO) twice a day on days 1 to 3. Patients in the control arm received the dexamethasone/ondansetron regimen and casopitant placebo. Depending on the particular casopitant arm assigned, patients received the following different doses and formulations of casopitant in addition to the dexamethasone/ondansetron combination: casopitant single oral dose (150 mg PO on day 1); casopitant 3-day oral dosage (150 mg PO on day 1 and 50 mg PO on days 2 and 3); or casopitant 3-day IV/oral dosage (90 mg IV on day 1 and 50 mg PO on days 2 and 3). Patients and the clinical staff involved in their treatment were blinded regarding whether a dose included casopitant or placebo. Provided that patients continued to meet inclusion criteria, they were permitted to participate in the study for up to four chemotherapy cycles.
The study protocol and amendments and informed consent documents were reviewed and approved by an independent ethics committee or institutional review board. Patients provided written consent before participation in the trial. All investigators were required to abide by Good Clinical Practices,15 International Conference on Harmonisation16 guidelines, Declaration of Helsinki principles, and local laws and regulations.
Patients were provided with diaries for the first 120 hours after a cycle of MEC and instructed to record emetic events, including the date, time, and number of events, and the use of any rescue medications, and to complete daily visual analog scale (VAS) nausea ratings. Use of rescue medication for the treatment of nausea or vomiting was at the discretion of the investigator and patient. Here we report findings from the first cycle of chemotherapy.
Adverse events and serious adverse events, regardless of relation to casopitant, were reported and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.
The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC. If a casopitant arm was superior to the control arm, the secondary end points of acute (0 to 24 hours) and delayed (24 to 120 hours) complete response were tested hierarchically for significance, with the acute phase of the complete response being first in the hierarchy. If an end point failed and was not statistically significant, then hierarchical testing stopped; subsequent comparisons are reported with P values for descriptive purposes only. The hypothesis was that all casopitant doses would be superior to ondansetron and dexamethasone alone.
The study had 90% power to detect a 12% absolute difference in overall complete response between the control arm and any of the casopitant arms, assuming a predicted 50% complete response rate at 120 hours for the control arm, with a level of significance of .0167 (two-sided and adjusted for three independent comparisons), requiring 460 patients per arm using the Cochran-Mantel-Haenszel test.
Secondary end points included the proportion of patients achieving acute and delayed complete response, no vomiting overall (0 to 120 hours), no vomiting in the acute (0 to 24 hours) and delayed (24 to 120 hours) phases, no nausea (VAS < 5 mm), no significant nausea (VAS < 25 mm), complete protection (complete response and no significant nausea), and total control (complete response and no nausea). Time to the first emetic event was also reported.
The baseline characteristics of this patient population were generally balanced across arms (Table 2).
|
| Characteristic | Control (n = 483) | Casopitant | ||
|---|---|---|---|---|
| Single Oral Dose (n = 483) | 3-Day Oral (n = 483) | 3-Day IV/Oral (n = 484) | ||
| Female, % | 98 | 98 | 98 | 98 |
| Median age, years | 52 | 51 | 51 | 53 |
| Race, % | ||||
| Asian | 19 | 21 | 26 | 22 |
| White/European | 74 | 73 | 70 | 71 |
| Other | 7 | 6 | 4 | 7 |
| Tumor type, % | ||||
| Breast cancer | 95 | 96 | 97 | 95 |
| Other | 5 | 4 | 3 | 5 |
| ECOG PS, % | ||||
| 0 | 81 | 83 | 84 | 81 |
| 1 | 18 | 16 | 14 | 18 |
| 2 | < 1 | < 1 | < 1 | < 1 |
| Chemotherapy, % | ||||
| Cyclophosphamide | > 99 | > 99 | > 99 | > 99 |
| Mean dose, mg/m2 | 985 | 975 | 955 | 971 |
| SD | 154 | 153 | 152 | 170 |
| Doxorubicin | 72 | 67 | 69 | 67 |
| Epirubicin | 28 | 33 | 30 | 33 |
| Fluorouracil | 37 | 40 | 41 | 40 |
Abbreviations: IV, intravenous; ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation.
Of the 1,933 patients randomly assigned to the study, a modified intent to treat (mITT) population (n = 1,917) was used for the efficacy analysis; the mITT population included all patients who were randomly assigned to a study arm, received investigational product, and had MEC administered (Fig 1).
Fig 1. CONSORT diagram. Patient disposition during the study. Patients identified as no completion/no discontinuation (disc) did not complete cycle 1 but did continue other cycles. MEC, moderately emetogenic chemotherapy; IV, intravenous.
Among patients receiving AC-based MEC, a statistically significant improvement in the proportion of patients achieving overall complete response was observed with the addition of casopitant to the ondansetron/dexamethasone regimen; the overall complete response improved from 59% in the control arm to 73% (odds ratio [OR] = 1.88; 95% CI, 1.35 to 2.63) in the casopitant single oral dose arm, 74% (OR = 1.92; 95% CI, 1.38 to 2.69) in the casopitant 3-day IV/oral arm, and 73% (OR = 1.85; 95% CI, 1.32 to 2.57) in the casopitant 3-day oral arm (P < .0001; Fig 2).
Fig 2. Complete response at 120 hours. P values were less than .0001 for all casopitant arms compared with the control arm. IV, intravenous.
There was no statistically significant difference between casopitant plus ondansetron and dexamethasone groups and the control group in the proportion of patients achieving complete response during the acute phase; 85% of patients in the control group, 88% of the patients in the casopitant single oral dose arm (P = .1586), 89% of the patients in the casopitant 3-day oral arm (P = .0545), and 86% of the patients in the casopitant 3-day IV/oral arm (P = .5835) achieved complete response during the acute phase. Per the hierarchical testing protocol, testing for statistical significance stopped. A numerical improvement in the proportion of patients who achieved complete response during the delayed phase was observed when comparing patients in the control arm with patients in the casopitant arms: 59% of patients in the control arm achieved delayed complete response versus 73% of the patients in the casopitant single oral dose arm, 73% of the patients in the casopitant 3-day oral dosage arm, and 74% of the patients in the casopitant 3-day IV/oral dosage arm. In addition, few patients (approximately 10%) experienced their first emetic event in the delayed phase in the casopitant groups, as compared with approximately 23% of patients in the control arm.
The proportion of patients achieving no nausea and no significant nausea during the overall phase was similar across all arms of the study, as was the proportion of patients achieving overall complete control and overall complete protection. Addition of casopitant to ondansetron and dexamethasone increased the proportion of patients reporting no vomiting overall (0 to 120 hours); more patients in the single oral dose, 3-day oral, and 3-day IV/oral casopitant arms achieved no vomiting (80%, 81%, and 78%, respectively) compared with the control arm (63%; P < .0001; Table 3). The time to first emetic event was generally similar across treatment groups in the first 8 to 12 hours after the first cycle of MEC, after which time a separation of curves between control and the casopitant groups becomes apparent. Posthoc pair-wise comparisons of the casopitant treatment and control groups were statistically significant (P < .0001; Fig 3).
|
| Efficacy End Point | Control (n = 479) | Single Oral Dose Casopitant (n = 479) | 3-Day Oral Casopitant (n = 480) | 3-Day IV/Oral Casopitant (n = 479) |
|---|---|---|---|---|
| Overall complete response | 59 | 73* | 73* | 74* |
| Acute | 85 | 88 | 89† | 86 |
| Delayed | 59 | 73* | 73* | 74* |
| Overall no vomiting | 63 | 80* | 81* | 78* |
| Acute | 86 | 91‡ | 91§ | 88 |
| Delayed | 63 | 80* | 81* | 78* |
| Overall no significant nausea | 58 | 60 | 59 | 61 |
| Overall no nausea | 35 | 38 | 33 | 39 |
| Acute | 71 | 66 | 64 | 67 |
| Delayed | 35 | 38 | 33 | 39 |
| Overall complete protection | 50 | 54 | 52 | 57 |
| Overall total control | 33 | 37 | 32 | 38 |
Abbreviation: IV, intravenous.
*P < .0001 v control arm.
†P = .0545 v control arm.
‡P = .0428 v control arm.
§P = .0131 v control arm.
Fig 3. Kaplan-Meier estimate for time to first emetic event. P values were less than .0001 for all casopitant arms compared with the control arm. IV, intravenous.
The safety population (n = 1,920) included all patients randomly assigned to a study arm who received any investigational drug (casopitant or casopitant placebo).
Casopitant was generally well tolerated, and adding casopitant to ondansetron and dexamethasone did not increase the toxicity of the antiemetic regimen. The most commonly reported all-cause adverse events—neutropenia, alopecia, and fatigue—were balanced across treatment arms (Table 4). All other adverse event rates were less than 10% and were balanced across treatment arms. The incidence of adverse events leading to patient discontinuation during cycle 1 was low and balanced across treatment arms: 0% in the casopitant 3-day oral dosage arm and 0.6% in all other arms.
|
| Event | % of Patients | |||
|---|---|---|---|---|
| Control (n = 479) | Single Oral Dose Casopitant (n = 481) | 3-Day Oral Casopitant (n = 481) | 3-Day IV/Oral Casopitant (n = 479) | |
| Any event | 76 | 77 | 80 | 79 |
| P * | — | .9109 | .2008 | .2438 |
| Neutropenia | 37 | 40 | 42 | 38 |
| Alopecia | 25 | 27 | 24 | 25 |
| Fatigue | 15 | 19 | 19 | 16 |
| Leukopenia | 18 | 16 | 17 | 17 |
| Constipation | 16 | 13 | 13 | 14 |
| Headache | 13 | 13 | 11 | 11 |
Abbreviation: IV, intravenous.
*Posthoc P values for comparison between each casopitant arm v control, using Pearson χ2 test.
To more clearly evaluate potential IV-associated adverse events, a supplemental analysis was performed that grouped preferred terms suggestive of an injection-site reaction into clinically meaningful categories. In this analysis, the incidence of infusion/injection-site reaction and infusion/injection-site pain was balanced across treatment arms (site reaction: 0% in the control and 3-day casopitant oral arms, < 1% in the single oral casopitant arm, and 1% in the 3-day IV/oral arm; site pain: 2% in the 3-day IV/oral arm, ≤ 1% in the other arms). The majority of these events occurred on day 1 of a cycle of chemotherapy and was grade 1 or 2 in severity, with a reported duration of 1 day or less.
The incidence of serious adverse events was balanced across treatment arms (4% in the control, 4% casopitant single oral dose, 4% casopitant 3-day oral, and 3% casopitant 3-day IV/oral). The rate of febrile neutropenia was 1% in the control arm, less than 1% in the casopitant single oral dose arm (P = .3412, Fisher's exact test), 1% in the casopitant 3-day oral arm (P = .3412), and 2% in the casopitant 3-day IV/oral arm (P = .2239). There was a single death in each study arm, none of which were attributed to the investigational drug by the investigator.
With 1,917 patients included in the mITT population, this is the largest prospective, randomized study published to date investigating the effect of antiemetics on CINV. This trial evaluated whether addition of casopitant to ondansetron and dexamethasone could improve the prevention of CINV in a population receiving an AC-based MEC regimen. The population was predominantly composed of females (98%) with breast cancer (96%). Despite advances in antiemetic therapy, a significant number of patients with breast cancer who receive AC-based MEC still experience nausea and vomiting at some point during chemotherapy.17
This trial demonstrated that administration of a three-drug antiemetic regimen with the first cycle of chemotherapy prevented CINV events in a significantly greater proportion of patients compared with the control (two-drug) arm as measured by complete response over 5 days. A previous study using a 3-day regimen of another NK1 receptor antagonist, aprepitant, demonstrated an improvement from 42% complete response to 51% complete response when added to ondansetron and dexamethasone in women with breast cancer receiving cyclophosphamide and anthracycline.12 The current study reported here, however, is the first phase III trial in the MEC setting in which efficacy was demonstrated with a single oral dose of an NK-1 receptor antagonist. Patients who received casopitant on days 2 and 3 did not appear to derive additional efficacy over those treated with casopitant on day 1 only, as demonstrated by the similar CR rates observed across the three experimental arms. However, the regimen of IV casopitant on day 1 followed by oral dosing on day 2 through 3 allows for flexibility indosing route on the day of chemotherapy without loss of antiemetic efficacy in the delayed phase.
The results presented here are consistent with research on the time course of the antiemetic effect of 5-HT3 and NK-1 receptor antagonists, which suggests that events occurring after the first 8 to 12 hours are primarily mediated by substance P and, therefore, are responsive to NK-1 receptor antagonists.8 A single oral dose of casopitant provides greater than 90% receptor occupancy for more than 60 hours.18 However, the degree of NK-1 receptor occupancy that provides optimal prevention of CINV remains unknown, as does the time course of receptor occupancy required for prevention of delayed nausea and vomiting.
Prevention of nausea and vomiting in the delayed phase is an important goal, as 52% of patients who receive MEC and antiemetic prophylaxis with a serotonin antagonist and a corticosteroid will experience delayed nausea and 28% experience delayed vomiting.2 In this trial, a larger proportion of patients in the casopitant arms achieved complete response and a larger proportion of patients in the casopitant arms did not vomit in the first 5 days after chemotherapy compared with patients in the control arm. The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant.
Casopitant was generally well tolerated; all-cause adverse events, drug-related adverse events, and serious adverse events were balanced across treatment arms. The incidence of adverse event terms suggestive of an injection-site reaction was balanced across treatment arms for patients receiving a MEC regimen with or without casopitant. These events did not result in a delay of chemotherapy administration.
More than 15 years after the introduction of 5-HT3 receptor antagonists, nausea and vomiting continue to be among the most feared symptoms of chemotherapy.1 The statistically significant benefit demonstrated in this study represents another important advance in the improvement of supportive care for patients with cancer. These benefits were demonstrated with a single oral dose of casopitant in combination with a 5-HT3 receptor antagonist and a single dose of dexamethasone. Furthermore, casopitant demonstrated an acceptable safety profile and was generally well tolerated in this population receiving AC-based MEC. This is the first phase III trial to demonstrate that a single dose of an NK-1 receptor antagonist provides superior prevention of CINV for 5 days in patients receiving MEC along with standard two-drug antiemetic treatment.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical trial information can be found for the following: NCT00366834.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under 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: Mark W. Russo, GlaxoSmithKline (C); Jeremey Levin, GlaxoSmithKline (C); Salabha Ranganathan, GlaxoSmithKline (C); Mary Guckert, GlaxoSmithKline (C) Consultant or Advisory Role: Jørn Herrstedt, Helsinn (C), Schering-Plough (C), GlaxoSmithKline (C); Simon Van Belle, GlaxoSmithKline (C); Steven M. Grunberg, GlaxoSmithKlein (C), Merck (C), Schering-Plough (C), Helsinn (C) Stock Ownership: Mark W. Russo, GlaxoSmithKline; Jeremey Levin, GlaxoSmithKline; Salabha Ranganathan, GlaxoSmithKline; Mary Guckert, GlaxoSmithKline; Steven M. Grunberg, Schering-Plough Honoraria: Jørn Herrstedt, Merck; Fausto Roila, GlaxoSmithKline; Steven M. Grunberg, Merck Research Funding: Jørn Herrstedt, Merck; Fausto Roila, GlaxoSmithKline; Steven M. Grunberg, Merck Expert Testimony: None Other Remuneration: None
Conception and design: Jørn Herrstedt, Mary Guckert, Steven M. Grunberg
Provision of study materials or patients: Jørn Herrstedt, Ahmed Shaharyar, Mary Guckert
Collection and assembly of data: Jørn Herrstedt, Ahmed Shaharyar, Zeba Aziz, Mary Guckert
Data analysis and interpretation: Jørn Herrstedt, Zeba Aziz, Mary Guckert, Steven M. Grunberg
Manuscript writing: Jørn Herrstedt, Ahmed Shaharyar, Zeba Aziz, Fausto Roila, Mary Guckert, Steven M. Grunberg
Final approval of manuscript: Jørn Herrstedt, Wichit Apornwirat, Ahmed Shaharyar, Zeba Aziz, Fausto Roila, Simon Van Belle, Mark W. Russo, Jeremey Levin, Salabha Ranganathan, Mary Guckert, Steven M. Grunberg
| 1. | CC Sun, DC Bodurka, CB Weaver , etal: Rankings and symptom assessments of side effects from chemotherapy: Insights from experienced patients with ovarian cancer Support Care Cancer 13: 219– 227,2005 Crossref, Medline, Google Scholar |
| 2. | SM Grunberg, RR Deuson, P Mavros , etal: Incidence of chemotherapy-induced nausea and emesis after modern antiemetics Cancer 100: 2261– 2268,2004 Crossref, Medline, Google Scholar |
| 3. | CT Liau, NM Chu, HE Liu , etal: Incidence of chemotherapy-induced nausea and vomiting in Taiwan: Physicians' and nurses' estimation vs. patients' reported outcomes Support Care Cancer 13: 277– 286,2005 Crossref, Medline, Google Scholar |
| 4. | N Neymark, R Crott: Impact of emesis on clinical and economic outcomes of cancer therapy with highly emetogenic chemotherapy regimens: A retrospective analysis of three clinical trials Support Care Cancer 13: 812– 818,2005 Crossref, Medline, Google Scholar |
| 5. | JL Richardson, G Marks, A Levine: The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy J Clin Oncol 6: 1746– 1752,1988 Link, Google Scholar |
| 6. | L Cohen, CA de Moor, P Eisenberg , etal: Chemotherapy-induced nausea and vomiting: Incidence and impact on patient quality of life at community oncology settings Support Care Cancer 15: 497– 503,2007 Crossref, Medline, Google Scholar |
| 7. | FM Schnell: Chemotherapy-induced nausea and vomiting: The importance of acute antiemetic control Oncologist 8: 187– 198,2003 Crossref, Medline, Google Scholar |
| 8. | PJ Hesketh, S Van Belle, M Aapro , etal: Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists Eur J Cancer 39: 1074– 1080,2003 Crossref, Medline, Google Scholar |
| 9. | M Marty, P Pouillart, S Scholl , etal: Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis N Engl J Med 322: 816– 821,1990 Crossref, Medline, Google Scholar |
| 10. | S Poli-Bigelli, J Rodrigues-Pereira, AD Carides , etal: Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: Results from a randomized, double-blind, placebo-controlled trial in Latin America Cancer 97: 3090– 3098,2003 Crossref, Medline, Google Scholar |
| 11. | PJ Hesketh, SM Grunberg, RJ Gralla , etal: The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group J Clin Oncol 21: 4112– 4119,2003 Link, Google Scholar |
| 12. | DG Warr, PJ Hesketh, RJ Gralla , etal: 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 Link, Google Scholar |
| 13. | W Arpornwirat, I Albert, VL Hansen , etal: Multicenter, randomized, double-blind, ondansetron (ond)-controlled, dose-ranging, parallel group trial of the neurokinin-1 receptor antagonist (NK-1 RA) casopitant mesylate for chemotherapy-induced nausea/vomiting (CINV) in patients (pts) receiving moderately emetogenic chemotherapy (MEC) J Clin Oncol 24: 471s,2006 abstr 8512 Google Scholar |
| 14. | SM Grunberg, D Osoba, PJ Hesketh , etal: Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity: An update Support Care Cancer 13: 80– 84,2005 Crossref, Medline, Google Scholar |
| 15. | E6 Good clinical practice: Consolidated guidance. ICH April 1996 Center for Drug Evaluation and Research http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf Google Scholar |
| 16. | International Conference on Harmonisation: Guidelines. https://www.ich.org/cache/html/250-272-1.html Google Scholar |
| 17. | CM Booth, M Clemons, G Dranitsaris , etal: Chemotherapy-induced nausea and vomiting in breast cancer patients: A prospective observational study J Support Oncol 5: 374– 380,2007 Medline, Google Scholar |
| 18. | BM Johnson, JF Hoke, RR Bandekar , etal: Pharmacokinetics and pharmacokodynamics of casopitant, an NK-1 receptor antagonist, in patients undergoing treatment with moderately and highly-emetogenic chemotherapy Clin Pharmacol Ther 2007 81: abstr Google Scholar |
Acknowledgment
We thank Susan Kralian, PhD, of Ogilvy Healthworld, for writing and editorial support. We thank the nearly 200 clinical investigators from Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Croatia, the Czech Republic, Denmark, Estonia, Germany, Greece, Hong Kong, Hungary, India, Ireland, Italy, Korea, Latvia, Lithuania, Mexico, Pakistan, Peru, The Philippines, Poland, the Russian Federation, Slovakia, South Africa, Spain, Taiwan, Thailand, the United Kingdom, and the United States for their contribution.
