Palonosetron, second generation 5-HT3 antagonist: a new perspective in CINV management

It is well established that the majority of cancer patients who undergo moderately or highly emetogenic cytotoxic treatment without receiving prophylactic antiemetics will experience chemotherapy-induced nausea and vomiting (CINV). Although the exact mechanisms of CINV are not fully known, it is clear from preclinical experiments and more than 15 years of clinical investigations that serotonin plays a major role in initiating nausea and vomiting associated with emetogenic chemotherapy. Emetogenic chemotherapy damages the gastrointestinal mucosa, causing the release of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells in the small intestine, which, in turn, activates 5-HT3 receptors located on vagal afferents1. Activated vagal afferent fibres send signals to the brain stem vomiting centers, initiating emesis1. The introduction of 5-HT3 receptor antagonists into clinical oncology in the 1990s led to significant improvements in control rates for acute nausea and vomiting associated with emetogenic chemotherapy, and 5-HT3 receptor antagonists are now considered part of the standard of care. As single agents for antiemetic prophylaxis of acute CINV (occurring within 24 hours of chemotherapy) in patients receiving moderately emetogenic chemotherapy, 5-HT3 receptor antagonists are reported to have complete response (CR) rates (i.e., no emesis, no use of rescue medication) of 50–70%2. Although they are commonly prescribed after the first day of chemotherapy, the effectiveness of 5-HT3 receptor antagonists as single agents in preventing delayed CINV is less well established. Four 5-HT3 receptor antagonists are currently approved for use in the United States and/or Europe: ondansetron, granisetron, tropisetron, and dolasetron. These agents have some pharmacologic differences in receptor binding affinity, selectivity, and metabolism. Despite these nuances, the minor pharmacologic differences of these agents have not translated into clinically meaningful differences among them. Therefore, according to current evidence-based guidelines (American Society of Clinical Oncology, Multinational Association of Supportive Care in Cancer) and consensus guidelines (American Society of Health-System Pharmacists, National Comprehensive Cancer Network), these 5-HT3 receptor antagonists are considered therapeutically equivalent and interchangeable when used at equipotent doses3–7. Although 5-HT3 receptor antagonists are part of the current standard of care for patients receiving chemotherapy, a substantial proportion of patients today continue to experience both acute and particularly delayed CINV after moderately or highly emetogenic chemotherapy7,8. Therefore, there is still a need to develop new agents to improve control rates and patient care.