A Randomized Cross-over Trial of Granisetron and Dexamethasone ...

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therapy/ 1 ** There is controversy about the efficacy of DEX combined with a 5-HT3 receptor antagonist for delayed emesis. A randomized trial comparing tropisetron monotherapy on days 1-6 with a combination of tropisetron and DEX on days 1-6 showed that significantly more patients in the latter arm were free of delayed nausea or vomiting, 10 ' whereas a comparison of a combination of GRN and DEX for 6 days with one of MET and DEX for 6 days showed that patients treated with the latter combination had a tendency to suffer more episodes of vomiting. 11 ' Another important factor in controlling delayed emesis is the degree of acute emesis, though the mechanism is not fully understood. 1 ' 2) Thus, delayed emesis is not an isolated pehnomenon and should be studied in conjunction with antiemetic therapy in the acute and delayed phases. This study showed that DEX administered on day 1 enhanced the control of nausea and vomiting on day 2 as well as that on day 1. This result is consistent with that of a randomized trial of OND and DEX versus high-dose MET, DEX, and diphenhydramine on day 1 with MET and DEX on days 2-5, which also showed better control on day 2 in the OND and DEX arm. 7) In addition, the present results suggest that early use of DEX may contribute to prevention of delayed emesis. The mean number of vomiting episodes on day 2 did not differ significantly between the treatments. The power was calculated at 30% from the true difference in the treatments, 0.428, and the standard error, 0.27, suggesting that the number of patients was too small for a difference to be demonstrated. 8 ' However, we discontinued the trial because a significant difference was observed in the mean number of vomiting episodes on day 1 and in the VAS score on day 2. In this trial, one fourth of the patients refused to receive MET because of severe hiccups and/or restlessness. Repeated administration of MET seemed to increase the incidence and severity of these symptoms. Other effects were mild and self-limiting. Although a cross-over design has been commonly applied in trials of antiemetic drugs, 12 ' its limitation are also well recognized. 9 ' First, drop-outs tend to occur frquently, especially in trials of chemotherapy for non-small cell lung cancer because of the low response rate. In this trial, 9 (23%) of 40 patients were excluded from the evaluation of efficacy. The second problem is the unstable condition of patients with cancer. We excluded patients who had poor performance status, short life expectancy, or any condition which may have caused nausea and vomiting, consciousness disturbance, or alteration of mental status. Third, we should consider carry-over effect in trials of anti- DEXAMETHASONE FOR DELAYED EMESIS emetic agents because the psychological status induced by the first treatment may influence outcome. Testing for a carry-over effect using patient totals showed no evidence of such an effect in the number of vomiting episodes on day 1 or in the VAS score on day 2." However, a cross-over design should be considerably advantageous in trials of delayed emesis, because fewer patients are required to obtain the same degree of precision as a result of elimination of inter-patient variation. 8 ' Otherwise, many patients would be required before phase III studies could establish a standard treatment. In conclusion, addition of DEX to GRN on day 1 was of great benefit for the control of nausea on day 2. Although the regimen of GRN + DEX on day 1 with MET + DEX on days 2-5 was well tolerated and highly effective on day 1, antiemetic efficacy in the delayed phase was hot satisfactory. Further trials of delayed emesis is conjunction with acutue and delayed antiemetic regimens are warranted. Acknowledgments This study was supportd in part by Grants-in-Aid for Cancer Research (5S-1) from the Ministry of Health and Welfare, Japan. References 1) Del Favero A, Roila F, Tonato M: Reducing chemotherapy-induced nausea and vomiting: current perspectives and future possibilities. Drug Safety 9: 410-428, 1993 2) Gralla RJ: Antiemetic therapy. In Cancer: Principles & Practice of Oncology, 4th ed, DeVita VT, Hellman S, Rosenberg SA, eds, JB Lippincott Co, Philadelphia. p2338-2348, 1993 3) Kris MG, Gralla RJ, Clark RA, Tyson LB, O'Connell JP, Wertheim MS, Kelsen DP: Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 3: 1379-1384, 1985 4) Shinkai T, Saijo N, Eguchi K, Sasaki Y, Tamura T, Fujiwara Y, Mae M, Fukuda M, Ohe Y, Sasaki S, Nakagawa K, Minato K, Hong WS, Suemasu K: Control of cisplatin-induced delayed emesis with metoclopramide and dexamethasone: a randomized controlled trial. Jpn J Clin Oncol 19: 40-44, 1989 5) Kris MG, Gralla RJ, Tyson LB, Clark RA, Cirrincione C, Groshen S: Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 7: 108-114, 1989 6) Moreno I, Rosell R, Abad A, Barnadas A, Carles J, Ribelles N, Solano V, Font A: Comparison of three protracted antiemetic regimens for the control of 167 Downloaded from http://jjco.oxfordjournals.org/ by guest on March 26, 2013
delayed emesis in cisplatin-treated patients. Eur J Cancer 28A: 1344-1347, 1992 7) Italian Group for Antiemetic Research: Ondansetron + dexamethasone vs metoclopramide + dexamethasone + diphenhydramine in prevention of cisplatininduced emesis. Lancet 340: 96-99, 1992 8) Hills M, Armitage P: The two-period cross-over clinical trial. Br J Clin Pharmac 8: 7-20, 1979 9) Senn S: Cross-over Trials in Clinical Research. John Wiley & Sons Ltd, Chichester. 1993 10) Sorbe B, Hogberg T, Himmelmann A, Schmidt M, Raisanen I, Stockmeyer M, de Bruijn KM: Efficacy and tolerability of tropisetron in comparison with a combination of tropisetron and dexamethasone in SEKINE ET AL. the control of nausea and vomiting induced by cisplatin-containing chemotherapy. Eur J Cancer 30A: 629-634, 1994 11) Ohmatsu H, Eguchi K, Shinkai T, Tamura T, Ohe Y, Nisio M, Kunikane H, Arioka H, Karato A, Nakashima H, Sasaki Y, Tajima K, Tada N, Saijo N: A randomized cross-over study of high-dose metoclopramide plus dexamethasone versus granisetron plus dexamethasone in patients receiving chemotherapy with high-dose cisplatin. Jpn J Cancer Res 85: 1151-1158, 1994 12) Bakowski MT: Advances in anti-emetic therapy. Cancer Treat Rev 11: 237-256, 1984 168 Jpn J Clin Oncol 26(3) 1996 Downloaded from http://jjco.oxfordjournals.org/ by guest on March 26, 2013
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