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www.TheOncologyPharmacist.com mended doses, with the most commonly observed adverse events being headache and constipation.8-10 Transient elevations in hepatic enzymes and potential QTc prolongation have also been reported in some patients.8-10 All of these 5-HT3 RAs are recommended for the prevention of acute CINV, with palonosetron also having data to support its use in the management of delayed CINV.8-10 Dolasetron is available as both an intravenous (IV) and oral formulation. Ondansetron is approved in a variety of oral formulations as well as an injectable formulation. Granisetron can be administered as either an oral or injectable formulation, and was also recently approved as a transdermal patch, indicated for 5 consecutive days of therapy. Both oral and IV formulations of palonosetron have been approved by the US Food and Drug Administration; however, only the injectable formulation is currently available in the United States. Single-dose schedules of 5-HT3 RAs are as effective as multidose schedules, and the oral formulations are therapeutically equivalent to the IV formulations.4,8-10 Although the advent of dolasetron, ondansetron, and granisetron represents a significant advance in the prevention and treatment of acute CINV, the efficacy of these agents in the delayed CINV setting is minimal with highly emetogenic chemotherapy (HEC) and modest, at best, with moderately emetogenic chemotherapy (MEC).11 Therefore, these drugs are not recommended for delayed CINV associated with HEC in the most recent CINV guidelines; however, they do remain an option for delayed emesis in patients receiving MEC. Palonosetron differs from first-generation agents in that it has a 100-fold higher binding affinity for the 5-HT3 receptor and a longer half-life (40 hours).10 Several trials have compared palonosetron with other 5-HT3 RAs. Aapro and colleagues compared palonosetron (0.25 mg or 0.75 mg) with ondansetron (32 mg) in patients receiving HEC.12 In this trial, dexamethasone was also administered at investigator discretion. Overall, there was no significant difference between palonosetron and ondansetron in the control of acute or delayed emesis. However, a post-hoc secondary subgroup analysis of the patients who received dexamethasone showed better control of acute and delayed emesis with palonosetron.12 In another phase 3 trial, Saito and colleagues compared palonosetron 0.75 mg with granisetron 40 µg/kg prior to chemotherapy on day 1.13 All patients in this trial received dexamethasone 16 mg on day 1, followed by additional doses on days 2 and 3. The complete response rate in the acute CINV phase was similar for palonosetron and granisetron (75% and 73%, respectively).13 However, in the de -
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layed CINV phase, the complete response rate was 57% for palonosetron and 45% for granisetron (P <.0001). Until recently, consensus guidelines for CINV have listed all of the 5-HT3 RAs as equivalent, with no preferences for use. However, the Multinational Association for Supportive Care in Cancer (MASCC) has now updated its guidelines to recommend palonosetron as the 5-HT3 RA of choice for MEC.9 Ongoing challenges in CINV control Several resources, including guidelines published by MASCC, the National Comprehensive Cancer Network (NCCN), and the American Society of Clinical Oncology (ASCO), are available to help guide clinicians in the management of CINV.8-10 All of these recommendations are developed by multidisciplinary teams of pharmacy, nursing, and physician practitioners and, in general, many similarities exist among these guidelines. Despite the availability of these and other resources, challenges related to the treatment of CINV still exist, including the management of delayed, breakthrough, and refractory symptoms, and appropriate strategies for patients receiving multiday chemotherapy.
Delayed CINV continues to be an issue, even when consensus guidelines are followed.
Delayed, breakthrough, and refractory CINV Delayed CINV continues to be an issue, even when consensus guidelines are followed. Novel agents such as palonosetron and the NK-1 RA, aprepitant, have shown efficacy in reducing the incidence of delayed CINV and are indicated for use in this setting; however, some patients still experience symptoms. MASCC, NCCN, and ASCO guidelines recommend scheduled prophylaxis for delayed CINV associated with highly and moderately emetogenic single-day regimens. For patients who experience delayed CINV despite optimal antiemetics, however, there are no clear recommendations. Therefore, utilization of agents with a different mechanism of action should be considered and, if effective, should be incorporated into a patient’s subsequent cycles of therapy. Likewise, the guidelines cite no preferred agents for breakthrough or refractory CINV. Therefore, treatment with agents from drug classes not currently being utilized in the patient’s existing antiemetic regimen may be a viable option.
Chemoreceptor Trigger Zone Cerebral Cortex
Visceral Afferents Vomiting Center
Salivary Receptors
Cranial Nerves
Abdominal Muscles
Respiratory Center
Source: Reference 3.
Figure. Pathway to Emesis
Multiday chemotherapy Many patients with cancer receive multiday chemotherapy, which presents additional CINV management challenges. These regimens are complicated by the overlap of acute and delayed emesis in addition to varying levels of emetogenicity which may occur throughout the course of treatment. Basic CINV treatment principles apply to these situations, such as ensuring that the daily level of emetogenicity (acute or delayed) is matched with the appropriate antiemetic; continued assessment of efficacy; and individualization of antiemetic regimens. However, it has yet to be determined how to best utilize newer agents, such as aprepitant and palonosetron, in these multiday regimens. For 5-day cisplatin regimens, for example, there is data to show that palonosetron dosing on days 1, 3, and 5 is effective.14 However, for non–cisplatin-based combinations or other multiday regimens, the dosing strategy is not as clear. Incorporating agents such as aprepitant also poses a challenge since it is not clear how NK-1 RAs should be scheduled with multiday chemotherapy. Current guidelines recommend starting aprepitant on day 1 of the multiday regimen; however, there is not sufficient data to verify that this or any other dosing strategy is preferable. In addition, there is some evidence suggesting that dosing beyond 3 days is safe, but improvement in efficacy has not yet been demonstrated with this approach.10,15 Conclusion Much has been learned about the etiology of CINV over the past several years, which has led to great strides in the prevention and management of symptoms. New agents have increased our armamentarium, but there is still room for improvement, especially in the areas of delayed, breakthrough, and refractory symptoms, and the treatment of patients who receive multiday chemotherapy. A multidisciplinary approach to
the assessment and management of CINV will help patients receive the optimal benefits of therapy. ● References 1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer. 1997; 76:1055-1061. 2. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13(4):219-227. 3. Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology. 2004;18(10 suppl 6):9-14. 4. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-2494. 5. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001;111(8 suppl 1):106S-112S. 6. Frame DG. Best practice management of CINV in oncology patients: I. Physiology and treatment of CINV. J Support Oncol. 2010;8(2 suppl 1):5-9. 7. del Giglio A, Soares HP, Caparroz C, et al. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy induced nausea and vomiting: results of a meta-analyses of randomized controlled trials. Cancer. 2000;89(11):2301-2308. 8. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: update 2006. J Clin Oncol. 2006;24:2932-2947. 9. Multinational Association for Supportive Care in Cancer. MASCC/ESMO Antiemetic Guidelines 2010. www.mascc.org. Accessed August 30, 2010. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Antiemesis, V.2.2010. April 7, 2010. http://www.nccn.org/profession als/physician_gls/PDF/antiemesis.pdf. 11. Geling O, Eichler H-G. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol. 2005;23(6):1289-1294. 12. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapyinduced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17(9):1441-1449. 13. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy randomized, comparative phase III trial. Lancet Oncol. 2009;10 (2):115-124. 14. Einhorn LH, Branes MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15(11):1293-1300. 15. de Wit R, Herrstedt J, Rapoport B, et al. The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebocontrolled phase III clinical trials. Eur J Cancer. 2004; 40(3):403-410.
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