Recent advances in antiemetics: new formulations of 5HT 3 -receptor antagonists

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Abstract

Purpose

To discuss new therapeutic strategies for chemotherapy-induced nausea and vomiting (CINV) involving 5-hydroxytryptamine type 3 (5HT ₃)-receptor antagonists (RAs).

Summary

CINV remains poorly controlled in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC); nausea and delayed-phase CINV (24–120 hours after chemotherapy) are the most difficult to control. National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) antiemesis-guideline recommendations for HEC include a four-drug regimen (5HT ₃ RA, neurokinin 1 [NK ₁] RA, dexamethasone, and olanzapine). For some MEC regimens, a three-drug regimen (5HT ₃ RA, NK ₁ RA, and dexamethasone) is recommended. While 5HT ₃ RAs have dramatically improved CINV in the acute phase (0–24 hours after chemotherapy), their efficacy declines in the delayed phase. Newer formulations have been developed to extend 5HT ₃-RA efficacy into the delayed phase. Granisetron extended-release subcutaneous (GERSC), the most recently approved 5HT ₃ RA, provides slow, controlled release of therapeutic granisetron concentrations for ≥5 days. GERSC is included in the NCCN and ASCO guidelines for MEC and HEC, with NCCN-preferred status for MEC in the absence of an NK ₁ RA. Efficacy and safety of 5HT ₃ RAs in the context of guideline-recommended antiemetic therapy are reviewed.

Conclusion

Recent updates in antiemetic guidelines and the development of newer antiemet-ics should help mitigate CINV, this dreaded side effect of chemotherapy. GERSC, the most recently approved 5HT ₃-RA formulation, is indicated for use with other antiemetics to prevent acute and delayed nausea and vomiting associated with initial and repeat courses of MEC and anthracycline–cyclophosphamide combination-chemotherapy regimens.

Related collections

Most cited references 113

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Antiemetics: American Society of Clinical Oncology clinical practice guideline update.

Ethan Basch, Ann Prestrud, Paul J Hesketh … (2011)

To update the American Society of Clinical Oncology (ASCO) guideline for antiemetics in oncology. A systematic review of the medical literature was completed to inform this update. MEDLINE, the Cochrane Collaboration Library, and meeting materials from ASCO and the Multinational Association for Supportive Care in Cancer were all searched. Primary outcomes of interest were complete response and rates of any vomiting or nausea. Thirty-seven trials met prespecified inclusion and exclusion criteria for this systematic review. Two systematic reviews from the Cochrane Collaboration were identified; one surveyed the pediatric literature. The other compared the relative efficacy of the 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists. Combined anthracycline and cyclophosphamide regimens were reclassified as highly emetic. Patients who receive this combination or any highly emetic agents should receive a 5-HT(3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK(1)) receptor antagonist. A large trial validated the equivalency of fosaprepitant, a single-day intravenous formulation, with aprepitant; either therapy is appropriate. Preferential use of palonosetron is recommended for moderate emetic risk regimens, combined with dexamethasone. For low-risk agents, patients can be offered dexamethasone before the first dose of chemotherapy. Patients undergoing high emetic risk radiation therapy should receive a 5-HT(3) receptor antagonist before each fraction and for 24 hours after treatment and may receive a 5-day course of dexamethasone during fractions 1 to 5. The Update Committee noted the importance of continued symptom monitoring throughout therapy. Clinicians underestimate the incidence of nausea, which is not as well controlled as emesis.

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In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Manag Res

Journal ID (iso-abbrev): Cancer Manag Res

Journal ID (publisher-id): Cancer Management and Research

Title: Cancer Management and Research

Publisher: Dove Medical Press

ISSN (Electronic): 1179-1322

Publication date Collection: 2018

Publication date (Electronic): 03 July 2018

Volume: 10

Pages: 1827-1857

Affiliations

[1 ]Clinical Services, Georgia Cancer Specialists, Atlanta, GA, USA, james.gilmore@ 123456gacancer.com

[2 ]Department of Clinical Pharmacy Services, New England Cancer Specialists, Scarborough, ME, USA

[3 ]West Virginia University Medicine, Morgantown, WV, USA

[4 ]West Cancer Center

[5 ]Division of Hematology/Oncology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

Author notes

Correspondence: James Gilmore, Georgia Cancer Specialists, 1835 Savoy Drive – suite 203, Atlanta, GA 30341, USA, Tel +1 770 496 9403, Fax +1 770 454 0548, Email james.gilmore@ 123456gacancer.com

Article

Publisher ID: cmar-10-1827

DOI: 10.2147/CMAR.S166912

PMC ID: 6037149

SO-VID: 28fdcf3f-d452-48ea-bbe0-1cf1070cba5c

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