Cancer Res Treat.  2013 Sep;45(3):172-177.

A Phase II Study to Evaluate the Efficacy of Ramosetron, Aprepitant, and Dexamethasone in Preventing Cisplatin-Induced Nausea and Vomiting in Chemotherapy-Naive Cancer Patients

• Jang G
• Song HH
• Park KU
• Kim HS
• Choi DR
• Kwon JH
• Kim HY
• Han B
• Kim JH
• Jung JY
• Kim HJ
• Zang DY

Abstract

PURPOSE
Combination therapy with aprepitant, serotonin receptor antagonist, and steroids improves the complete response rate of both acute and delayed chemotherapy-induced nausea and vomiting (CINV). However, it is not known whether ramosetron is suitable for administration in combination with aprepitant. Therefore, we conducted a multicenter, open-label, prospective, phase II study in order to assess the efficacy and tolerability of combination therapy with ramosetron, aprepitant, and dexamethasone (RAD) for prevention of cisplatin-based CINV in chemotherapy-naive patients with solid cancers.
MATERIALS AND METHODS
Forty-one patients with various solid cancers (31 male and 10 female; median age, 59 years) who received treatment with highly emetogenic chemotherapy (median cisplatin dose, 70 mg/m2; range 50 to 75 mg/m2) were enrolled in this study. Oral aprepitant (125 mg on day 1; 80 mg on days 2 and 3), intravenous ramosetron (0.6 mg on day 1), and oral dexamethasone (12 mg on day 1; 8 mg on days 2-4) were administered for prevention of CINV.
RESULTS
The complete response (no emesisand retching and no rescue medication) rate was 94.9% in the acute period (24 hours post-chemotherapy), 92.3% in the delayed period (24-120 hours post-chemotherapy), and 92.3% in the overall period (0-120 hours). The absolute complete response (complete response plus no nausea) rate was 74.4% in the acute period, 51.3% in the delayed period, and 46.2% in the overall period. There were no grade 3 or 4 toxicities related to these antiemetic combinations.
CONCLUSION
RAD regimen is a safe and effective antiemetic treatment for prevention of CINV in patients receiving highly emetogenic chemotherapy.

Keyword

Aprepitant; Dexamethasone; Ramosetron; Chemotherapy-induced nausea and vomiting

MeSH Terms

Benzimidazoles
Cisplatin
Dexamethasone
Humans
Male
Morpholines
Nausea
Prospective Studies
Serotonin
Steroids
Vomiting
Benzimidazoles
Cisplatin
Dexamethasone
Morpholines
Serotonin
Steroids

Reference

1. Osoba D, Zee B, Pater J, Warr D, Latreille J, Kaizer L. Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Determinants of postchemotherapy nausea and vomiting in patients with cancer. J Clin Oncol. 1997; 15:116–123. PMID: 8996132.

2. Pollera CF, Giannarelli D. Prognostic factors influencing cisplatin-induced emesis: definition and validation of a predictive logistic model. Cancer. 1989; 64:1117–1122. PMID: 2667749.

3. Booth CM, Clemons M, Dranitsaris G, Joy A, Young S, Callaghan W, et al. Chemotherapy-induced nausea and vomiting in breast cancer patients: a prospective observational study. J Support Oncol. 2007; 5:374–380. PMID: 17944146.

4. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: Antiemesis Version 1.2013. Fort Washington: National Comprehensive Cancer Network;2013.

5. Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010; 21(Suppl 5):v232–v243. PMID: 20555089.

6. Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011; 29:4189–4198. PMID: 21947834.

7. Hesketh PJ, Grunberg SM, Herrstedt J, de Wit R, Gralla RJ, Carides AD, et al. Combined data from two phase III trials of the NK1 antagonist aprepitant plus a 5HT 3 antagonist and a corticosteroid for prevention of chemotherapy-induced nausea and vomiting: effect of gender on treatment response. Support Care Cancer. 2006; 14:354–360. PMID: 16450086.

8. Jordan K, Kinitz I, Voigt W, Behlendorf T, Wolf HH, Schmoll HJ. Safety and efficacy of a triple antiemetic combination with the NK-1 antagonist aprepitant in highly and moderately emetogenic multiple-day chemotherapy. Eur J Cancer. 2009; 45:1184–1187. PMID: 19135359.

9. Herrington JD, Jaskiewicz AD, Song J. Randomized, placebo-controlled, pilot study evaluating aprepitant single dose plus palonosetron and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. Cancer. 2008; 112:2080–2087. PMID: 18327813.

10. Koizumi W, Tanabe S, Nagaba S, Higuchi K, Nakayama N, Saigenji K, et al. A double-blind, crossover, randomized comparison of granisetron and ramosetron for the prevention of acute and delayed cisplatin-induced emesis in patients with gastrointestinal cancer: is patient preference a better primary endpoint? Chemotherapy. 2003; 49:316–323. PMID: 14671433.

11. Cheirsilpa A, Sinthusake T, Songsakkaesorn A, Visawaprasit S, Chulaka K, Changkuingdee N. Comparison of ramosetron and granisetron for the prevention of acute and delayed emesis in cisplatin-based chemotherapy: a randomized controlled trial. Jpn J Clin Oncol. 2005; 35:695–699. PMID: 16319109.

12. Shi Y, He X, Yang S, Ai B, Zhang C, Huang D, et al. Ramosetron versus ondansetron in the prevention of chemotherapy-induced gastrointestinal side effects: a prospective randomized controlled study. Chemotherapy. 2007; 53:44–50. PMID: 17202811.

13. Kang YK, Park YH, Ryoo BY, Bang YJ, Cho KS, Shin DB, et al. Ramosetron for the prevention of cisplatin-induced acute emesis: a prospective randomized comparison with granisetron. J Int Med Res. 2002; 30:220–229. PMID: 12166338.

14. Borjeson S, Clark-Snow R, Rinley R, Gralla RJ, Kris MG, Rittenberg CN. MASCC antiemesis tool (MAT) [Internet]. Hillerod: Multinational Association of Supportive Care in Cancer;cited 2009 Jun 1. Available from: http://www.mascc.org/mc/page.do?sitePageId=88036 .

15. Villalon A, Chan V. Multicenter, randomized trial of ramosetron plus dexamethasone versus ramosetron alone in controlling cisplatin-induced emesis. Support Care Cancer. 2004; 12:58–63. PMID: 14655041.

16. Kim JH, Kim TW, Ryu MH, Chang HM, Lee SH, Lee JS, et al. A randomised crossover study comparing ramosetron plus dexamethasone with ramosetron alone in the prevention of cisplatin-induced emesis. Clin Drug Investig. 2005; 25:191–197.

17. A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001; 20:859–866. PMID: 11252008.

18. Voravud N, Sriuranpong V. Phase II trial of ramosetron plus dexamethasone in the prevention of cisplatin-induced nausea and vomiting. J Med Assoc Thai. 2005; 88:1790–1796. PMID: 16518975.

19. Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin: the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003; 21:4112–4119. PMID: 14559886.

20. Longo F, Mansueto G, Lapadula V, De Sanctis R, Quadrini S, Grande R, et al. Palonosetron plus 3-day aprepitant and dexamethasone to prevent nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2011; 19:1159–1164. PMID: 20552375.

21. Miyata K, Kamato T, Yamano M, Nishida A, Ito H, Katsuyama Y, et al. Serotonin (5-HT)3 receptor blocking activities of YM 060, a novel 4,5,6,7-tetrahydrobenzimidazole derivative, and its enantiomer in anesthetized rats. J Pharmacol Exp Ther. 1991; 259:815–819. PMID: 1941629.

22. Miyata K, Yamano M, Kamato T, Akuzawa S. Effect of serotonin (5-HT)3-receptor antagonists YM060, YM114 (KAE-393), ondansetron and granisetron on 5-HT4 receptors and gastric emptying in rodents. Jpn J Pharmacol. 1995; 69:205–214. PMID: 8699628.

23. Nakajima M, Kanamaru M, Miura H, Takeshige T, Atsuta Y. Phase I clinical study of YM060 in healthy male volunteers: single-dose intravenous administration. Jpn J Clin Exp Med. 1994; 71:2461–2468.

24. Roscoe JA, Heckler CE, Morrow GR, Mohile SG, Dakhil SR, Wade JL, et al. Prevention of delayed nausea: a University of Rochester Cancer Center Community Clinical Oncology Program study of patients receiving chemotherapy. J Clin Oncol. 2012; 30:3389–3395. PMID: 22915657.