69 4 CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING | PART TWO Introduction Chemotherapy-induced nausea and vomiting (CINV) in the delayed phase (24-120 hr post-chemotherapy) remains one of themost troublesome adverse effects associatedwith cancer treatment [1-4]. Clinical studies among patients receiving moderately emetogenic chemotherapy (MEC) demonstrate significantly higher incidences of delayed CINV compared with acute CINV (0-24 hr post-chemotherapy), with twice as many patients requiring rescue antiemetic therapy during the delayed phase [5-7]. In particular, delayed nausea is often poorly controlled; patients experience nausea as more distressing than vomiting [8, 9]. Nausea is also frequently underreported by patients leading to underestimation and undertreatment by clinicians [10, 11]. Many of the antiemetic agents currently available do little to relieve nausea [12]. Evidence-based antiemetic guidelines [13, 14] for patients receiving MEC recommend co-administration of a hydroxytryptamine-3 (5-HT3) receptor antagonist (RA) and dexamethasone (DEX). DEXbeyond24h is recommended for agentswith a knownpotential for delayed CINV such as oxaliplatin, monotherapy doxorubin or cyclophosphamide. This recommendation is based upon results from studies performed in patients receiving regimens, which have recently been reclassified as highly emetogenic chemotherapy, such as anthracycline / cyclophosphamide (AC) combinations and carboplatin [15, 16]. Although prophylactic DEX has been generally considered safe, its administration may be associated with a wide range of side effects in the week after the initiation of chemotherapy [17]. Therefore, there is interest in minimising dose and frequency of DEX in antiemetic regimens recommended for the prevention of acute and delayed CINV. A recent meta-analysis demonstrated that a DEX-sparing regimen consisting of single-dose DEX plus the second-generation 5-HT3 RA palonosetron compared with 3-day DEX plus palonosetron did not cause any significant loss in protection against not only vomiting but also nausea during the delayed period [18]. However, only two of the eight studies included in this analysis involved MEC [19, 20]. The primary endpoint in both studies was complete response (CR; defined as no emetic episodes, no rescue medication) in the overall 5-day study period, while no nausea or no more than mild nausea in the delayed phase were single secondary endpoints or part of composite secondary endpoints, for which these trials were not powered. The results may therefore not accurately reflect the patients’ actual experience of delayed nausea. Another DEX-sparing option to improve CINV outcomes in MEC-treated patients is the addition of a third prophylactic drug to the antiemetic backbone containing a 5-HT3 RA plus single-dose DEX. Receptors other than serotonergic, such as dopaminergic, histaminic and muscarinic may be the dominant receptors in the control of nausea [21-23]. Therefore, dopamine 2 (D2)-receptor antagonists with prokinetic effects like metoclopramide, currently recommended only for the treatment of breakthrough emesis, could be useful in improving delayed nausea control. Comparative studies in MEC-treated patients investigating the efficacy of a three-drug prophylactic antiemetic regimen including a dopamine receptor antagonist with a 5-HT3 RAplus single-doseDEX against delayed nausea are lacking so far. Herein we report the results of a randomized, phase III, noninferiority trial among patients receiving MEC, in which we studied the efficacy and safety of two
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