Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy

doi:10.1016/j.ejca.2008.11.046

European Journal of Cancer

Volume 45, Issue 7, May 2009, Pages 1184-1187

https://doi.org/10.1016/j.ejca.2008.11.046 Get rights and content

Abstract

Aim of the study

In multiple-day chemotherapy (MDC), the combination of a 5-HT₃-antagonist plus dexamethasone is still a standard of care. The role of a NK-1-antagonist remains to be defined.

Patients and methods

Seventy eight cancer patients undergoing multiple-day chemotherapy of high (HEC) or moderate (MEC) emetic risk received granisetron, dexamethasone plus aprepitant during chemotherapy. After the end of chemotherapy, aprepitant plus dexamethasone was given for another 2 days. Primary end-point was complete response (CR) in the overall phase (day 1 until 5 days after the end of chemotherapy).

Results

Thirty eight patients underwent HEC and 40 patients underwent MEC for a median of 3.5 days. CR was seen in 57.9% and 72.5% of patients receiving HEC and MEC, respectively. The tolerability of the aprepitant regimen over 5–7 days was comparable with a 3-day aprepitant regimen.

Conclusions

This is the first report in MDC with a NK-1-antagonist containing antiemetic regimen showing a favourable safety profile with good antiemetic efficacy.

Introduction

Chemotherapy-induced nausea and vomiting (CINV) are common side-effects of chemotherapy and still a great burden for cancer patients. In single-day chemotherapy, the antiemetic guidelines recommend the triple combination of a 5-HT₃-antagonist plus dexamethasone plus the NK-1-antagonist aprepitant in highly and moderately (AC-based) emetogenic chemotherapies.1, 2 However, this refers exclusively to single-day chemotherapy. In MDC, the use of a 5-HT₃-antagonist plus dexamethasone for acute CINV and dexamethasone alone for delayed CINV is still a standard of care.2, 3 The level of control with this antiemesis prophylaxis in 5-day cisplatin chemotherapy is still suboptimal, achieving acute CR’s (no emetic episodes, days 1–5) in the range of 55–58%.4, 5 In order to improve on these results, the addition of a NK-1-antagonist in MDC seems to be the next logical step to enhance the emetic control.

Section snippets

Design

This non-randomised single institution analysis of the triple combination of aprepitant, granisetron and dexamethasone in MDC was conducted at the university hospital in Halle, Germany within a 3-year period. The study was conducted in accordance with the Helsinki declaration and the guidelines on good clinical practice.

Patients

Patients were considered for this study if they were ⩾18 years and were intended for a MDC (3 or 5 days) of moderate or high emetogenic potential. Post hoc applied exclusion

Patients/chemotherapy

In the study period, 78 patients had received the scheduled aprepitant regimen, matched all criteria of the protocol, and were included in the final analyses. Baseline characteristics are summarised in Table 1. Patients with moderately emetogenic chemotherapies received cytostatics exclusively for 3 days and patients with highly emetogenic chemotherapies for 3 (45%) or 5 (55%) days (mean 4.1). Sixty-six%/85% of patients with highly/moderately emetogenic chemotherapy received a

Discussion

With the standard combination of a 5-HT₃-antagonist plus dexamethasone in 5-day cisplatin, MDC response rates between 55% and 58% can be achieved.4, 5 The role of a NK-1-antagonist in MDC remains to be defined.

In the latest study by Einhorn et al.⁶, the combination of palonosetron plus dexamethasone in 41 patients receiving 5-day cisplatin treatment achieved an acute/delayed CR of 34.1% and 61.0%, respectively. Palonosetron (0.25 mg i.v.) was applied on days 1, 3 and 5 and dexamethasone on days

Conclusions

This is the first report providing evidence for the favourable safety profile showing no cumulative or unexpected toxicity and good efficacy of the triple antiemetic combination of aprepitant, granisetron and dexamethasone in MDC. Compared to clinical data from the literature, aprepitant could provide additional benefit in preventing CINV during MDC.

Conflict of interest statement

K. Jordan∗: consultancies and received honoraria from Roche AG and MSD

I. Kinitz: none declared

W. Voigt: none declared

T. Behlendorf: none declared

H.-H. Wolf: none declared

H.-J. Schmoll: consultancies and received honoraria from Roche AG and MSD

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Evidence supports prophylactic use of olanzapine for the treatment of chemotherapy-induced nausea and vomiting (CINV). However, most studies to date have focused on patients with single-day highly emetogenic chemotherapy (HEC). Currently, administration of antiemetic therapies for nausea and vomiting induced by multiday chemotherapy regimens remains a challenge. In this study, we evaluated the efficacy of olanzapine combined with triple antiemetic therapy for the prevention of CINV in patients receiving multiday chemotherapy.
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Between December 2020 and September 2021, 349 patients with malignant solid tumors were enrolled in the study, with 175 participants randomly assigned to receive olanzapine and 174 participants assigned to receive placebo. The proportion of patients who achieved a complete response in the overall phase was significantly higher in the olanzapine group than in the placebo group (69% vs. 58%, P = 0.031). A complete response benefit was observed in the olanzapine group versus the placebo group in almost all the subgroups. Four factors were considered significantly associated with complete response in multivariable analysis: treatment group, gender, baseline plasma concentration of 5-HT, and prior radiotherapy. All the reported adverse events associated with olanzapine administration were grades 1 and 2.
Olanzapine (5 mg) combined with fosaprepitant, ondansetron, and dexamethasone was better than triple antiemetic therapy alone for patients receiving multiday chemotherapy regimens. Based on these results, the four-drug combination should be recommended as the best antiemetic regimen given to patients receiving multiday cisplatin-based chemotherapy and baseline plasma concentration of 5-HT may be used to identify individuals who are prone to CINV. However, all these findings need to be further validated in future studies.
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The risk of nausea and vomiting for a patient being treated with RT depends upon multiple other factors in addition to the emetogenicity of the specific RT regimen. Patient-specific factors include the simultaneous administration of chemotherapy as another prominent risk factor and also age, gender, alcohol consumption, anxiety, and previous experience of RINV or CINV (Table 2) (Feyer et al., 2005; Jordan et al., 2009; Maranzano, 2001). The four risk categories based upon the RT regimen can be modified to incorporate these patient-specific factors.
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Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy

Abstract

Aim of the study

Patients and methods

Results

Conclusions

Introduction

Section snippets

Design

Patients

Patients/chemotherapy

Discussion

Conclusions

Conflict of interest statement

Crit Rev Oncol Hematol

Lancet

Ann Oncol

Ann Oncol

American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006

J Clin Oncol