Abstract & Commentary
Synopsis: A single i.v. dose of palonosetron 0.25 mg was significantly superior to i.v. ondansetron 32 mg in the prevention of acute and delayed CINV.
Source: Gralla R, et al. Ann Oncol. 2003;14:1570-1577.The prevention of acute chemotherapy-induced nausea and vomiting (CINV) has improved dramatically in the past decade. Three selective 5-HT3 (serotonin-3) receptor antagonists—dolasetron, ondansetron, and granisetron—are available in the United States for this use. Despite some minor variations in pharmacology, these differences have not resulted in any clinically meaningful differences. According to current consensus guidelines, these medications are equivalent with regard to efficacy and are therapeutically interchangeable when used at equipotent doses.1 The efficacy of these drugs is high with reported response rates of 50-70% in the prevention of acute CINV. There is a significant clinical problem in the prevention of delayed CINV. Palonosetron is a highly potent, selective, second-generation 5-HT3 receptor antagonist with a binding affinity that is ~100 fold higher than other drugs of the same class. It has an extended plasma elimination half-life of ~40 hours, which is significantly longer than others in its class. The present study was designed to determine the efficacy of this drug in the prevention of acute and delayed CINV following administration of moderately emetogenic chemotherapy.
Comment by Stuart M. Lichtman, MD, FACP
Patients older than age 18 scheduled to receive moderately emetogenic chemotherapy were selected. The chemotherapy included any dose of carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan or mitoxantrone; methotrexate > 250 mg/m2; or cisplatin > 50 mg/m2; cyclophosphamide > 1500 mg/m2; or doxorubicin > 25 mg/m2. Patients were to receive a single intravenous dose of palonosetron 0.25 mg, palonosetron 0.75 mg, or ondansetron 32 mg.
Corticosteroids were not used in this trial. A complete response (CR) was defined as no emetic episode and no use of rescue medication during the first 24 hours following chemotherapy administration. Secondary end points included the proportion of patients achieving a CR during the delayed 24-120 hour time period and the cumulative 120-hour time period. Complete control was defined as no emetic episode, no need for rescue medication, and no more than mild nausea. Various quality-of-life parameters were also used.
The study had 563 patients evaluable for efficacy. The rate of CR with palonosetron 0.25 mg was superior to palonosetron 0.75 mg and ondansetron 32 mg in the prevention of acute (81% vs 73.5% vs 68.6%), delayed (74.1% vs 64.6% vs 55.1%), and overall (69.3% vs 58.7% vs 50.3%) CINV. Palonosetron produced significantly higher complete control rates compared with ondansetron during the delayed interval (66.7% vs 50.3%) and the overall interval (63.0% vs 44.9%). Time-to-treatment failure was significantly longer following treatment with palonosetron than treatment with ondansetron (46.5 hours vs 19.5 hours). Palonosetron 0.25 mg was superior to ondansetron in the number of emetic episodes during the acute, delayed, and overall intervals as well as on study days 2 and 3. Subset analysis showed than males had higher CR and complete control rates, less severe nausea, longer time to treatment failure, longer time to first emetic episode, and less rescue medication. Chemotherapy-naive patients tended to have less severe nausea than non-naive patients. The most common adverse reaction reported was headache in all groups (~5%).
The results of this study suggest that the binding affinity difference of palonosetron translates into improved control of CINV in patients receiving moderately emetogenic chemotherapy. This single-dose study showed the superiority of palonosetron over ondansetron in preventing delayed CINV, as measured by CR and complete control rates, as well as respect to number of emetic episodes, percent of patients with no nausea, and time to treatment failure. A similar trial of palonosetron and dolasetron in patients receiving moderately emetogenic chemotherapy showed similar results.2
This is an important clinical observation, as other 5-HT3 receptor antagonists do not demonstrate substantial efficacy in delayed emesis, despite repeated dosing and concomitant use with corticosteroids. There is currently available a novel neurokinin 1 antagonist, aprepitant, that has been shown to improve control of CINV when added to a standard antiemetic regimen of 5-HT3 receptors antagonists plus a corticosteroid.2 Aprpeitant can produce moderate inhibition of CYP3A4, which can potentially produce clinically significant drug interactions.3
There are now a number of newer and more efficacious medications for the prevention of acute and delayed CINV. Palonosetron may have an advantage in that it can be used as a single-dose medication, which does not require corticosteroids for efficacy. Further studies will elucidate the role of the second-generation 5-HT3 receptor antagonists and neurokinin 1 antagonists in the treatment of our patients.
Dr. Lichtman, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.
References
1. Gralla RJ, et al. J Clin Oncol. 1999;17:2971-2994.
2. Poli-Bigelli S, et al. Cancer. 2003;97:3090-3098.
3. Majumdar AK, et al. Clin Pharmacol Ther. 2003;74: 150-156.
The prevention of acute chemotherapy-induced nausea and vomiting (CINV) has improved dramatically in the past decade.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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