147 8 DELIRIUM | PART THREE Part Two: Chemotherapy-induced nausea and vomiting In Chapter 3 we describe the results of a systematic review of RCT’s investigating the efficacy of two or more antiemetic regimens for the prevention of delayed chemotherapyinduced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC). With a systematic search in PubMed and conference proceedings from the American Society of Clinical Oncology (ASCO), the Multinational Association for Supportive Care in Cancer (MASCC), and the European Society of Medical Oncology (ESMO), a total of 247 publications were identified. Of these, nine met the inclusion eligibility criteria [44-52]. When analysing the primary outcomes measured, we observed that most included RCT’s primarily focused on control of vomiting or the composite endpoint complete response (CR), defined as no vomiting and no use of rescue medications. Two studies compared the efficacy of the second-generation serotonin receptor antagonist (5-HT3 RA) palonosetron to first generation 5-HT3 RA’s [45, 46]. Both studies suggest that palonosetron is equally effective as first-generation 5-HT3 RA’s for the prevention of acute (0-24 hours after chemotherapy) and delayed (24-120 hours after chemotherapy) CINV after MEC. The addition of a neurokinin-1 receptor antagonist (NK1 RA) to first-generation 5-HT3 RA’s did not significantly improve CR rates during the acute and delayed phases in MEC-treated patients [47-49]. Dexamethasone, one of the first antiemetic drug to be introduced, is still widely used in multi-drug regimens recommended for thepreventionof acuteanddelayedCINVcausedby highly emetogenic chemotherapy or MEC. The mechanism of action of dexamethasone as antiemetic agent has not been elucidated, but it may be related to activity in the peripheral or central nervous system, and possibly by antagonizing serotonin receptors [53-56]. Tolerability to dexamethasone can be a concern, because when used for the prevention of delayed nausea and vomiting, common adverse effects have included insomnia, epigastric discomfort, agitation, weight gain, and hyperglycemia [57]. Therefore, there is interest in minimising dose and frequency. One multicenter open-label, noninferiority study was included in the systematic review that evaluated the efficacy of palonosetron plus single-day dexamethasone compared with multiday dexamethasone [44]. This study with CR during the overall phase (0-120 hours after chemotherapy) as primary endpoint included 332 patients receiving anthracycline / cyclophosphamide combinations or MEC (mainly oxaliplatin-, irinotecan-, and carboplatin-based regimens). Overall CR rates were 67.5% for those (n = 166) administered dexamethasone only on day 1, and 71.1% for those (n = 166) also administered dexamethasone on days 2 and 3 (difference-3.6%, 95% CI -13.5-6.3). CR rates were not significantly different between groups during the acute (88.6% versus 84.3%; p = 0.262) and delayed phases (68.7% versus 77.7%; p = 0.116). A confounding issue is that the outcomes used in this study might not reflect the patients’ actual experience of CINV, because the use of CR as a single dichotomous endpoint does not adequately capture the incidence of nausea. This is important, because the lack of complete nausea control is considered the greatest unmet need in CINV control [58, 59]. Nausea can be particularly prominent during the delayed period. A study of 240 patients receiving MEC demonstrated significantly higher incidences of delayed nausea and vomiting compared to acute nausea and vomiting, with twice as many patients requiring rescue antiemetic therapy during the delayed phase [60]. However, few studies have used
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