, Volume 55, Issue 2, pp 173–189 | Cite as

5-HT3 Receptor Antagonists for the Prevention of Chemotherapy-Induced Nausea and Vomiting

A Comparison of Their Pharmacology and Clinical Efficacy
Review Article


In the mid-1980s it was discovered that serotonin (5-hydroxytryptamine; 5-HT) was at least partially responsible for producing chemotherapy-induced nausea and vomiting. It was therefore realised that serotonin receptor blockade with serotonin 5-HT3 receptor antagonists could inhibit chemotherapy-induced nausea and vomiting.

5-HT3 antagonists have different chemical structures and receptor binding affinity. Granisetron, dolasetron and its major metabolite are pure 5-HT3 antagonists, while ondansetron and tropisetron are weak antagonists at the 5-HT4 receptor. Ondansetron has also been demonstrated to bind at other serotonin receptors and to the opioid µ receptor.

The half-lives of granisetron, tropisetron and the active metabolite of dolasetron are 2 to 3 times longer than that of ondansetron. These observations initially suggested that more frequent ondansetron administration would be required; however, it has now been shown that receptor blockade does not correlate with elimination half-life and all 5-HT3 antagonists can be effectively administered once daily.

Clinical trials have been conducted that directly compare the 5-HT3 antagonists. To compare these studies, it is necessary to assess trial design, including known risk factors for the development of chemotherapy-induced nausea and vomiting, and response criteria. Stratification for risk factors, use of strict efficacy criteria and randomisation to a blinded trial using an appropriate comparative regimen are essential for a well designed antiemetic trial.

Comparative clinical trials using various doses, routes and regimens of administration have been conducted with 5-HT3 antagonists. Despite some trial design shortcomings, most of the studies show equal efficacy between the agents, especially in moderately emetogenic chemotherapy and mild, infrequently occurring adverse effects. The addition of steroids also appears to improve outcome. However, since many doses and regimens of ondansetron were used, further study is needed to determine the optimal regimen.

The efficacy of 5-HT3 antagonists in controlling delayed nausea and vomiting from chemotherapy is less well studied. Further, there is no good scientific rationale for the use of 5-HT3 antagonists in controlling delayed nausea and vomiting since serotonin has not been shown to be released during the delayed phase. In fact, most studies show no benefit or modest benefit of 5-HT3 antagonists over placebo.

Because the 5-HT3 antagonists perform similarly in the clinical setting, pharmacological differences do not seem to translate into therapeutic differences. There is also no appreciable difference in the incidence or severity of adverse effects among the 5-HT3 antagonists. Determination of clinical use may then be driven by cost.


Adis International Limited Ondansetron Granisetron Tropisetron Emetogenic Chemotherapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Craig JB, Powell BL. The management of nausea and vomiting in clinical oncology. Am J Med Sci 1987; 293: 34–44PubMedCrossRefGoogle Scholar
  2. 2.
    Veyrat-Follet C, Farinotti R, Palmer JL. Physiology of chemotherapy-induced emesis and antiemetic therapy: predictive models for evaluation of new compounds. Drugs 1997 Feb; 53(2): 206–34PubMedCrossRefGoogle Scholar
  3. 3.
    Leslie RA. Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus. Neurochem Int 1985; 7: 191–211PubMedCrossRefGoogle Scholar
  4. 4.
    Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol 1986; 88: 497–9PubMedCrossRefGoogle Scholar
  5. 5.
    Andrews PLR, Rapeport WG, Sanger GJ. Neuropharmacology of emesis induced by anticancer therapy. Trends Pharmacol Sci 1988; 9: 334–41PubMedCrossRefGoogle Scholar
  6. 6.
    Leslie RA, Shah Y, Thejomayen M, et al. The neuropharmacology of emesis: the role of receptors in neuromodulation of nausea and vomiting. Can J Physiol Pharmacol 1990; 68: 279–88PubMedCrossRefGoogle Scholar
  7. 7.
    Alfieri AB, Cebeddu LX. Treatment with para-chlorophenylalanine antagonises the emetic response and the serotonin-releasing actions of cisplatin in cancer patients. Br J Cancer 1995; 71: 629–32PubMedCrossRefGoogle Scholar
  8. 8.
    Fozard JR. 5-HT3 receptors and cytotoxic drug-induced vomiting. Trends Pharmacol Sci 1987; 8: 44–5CrossRefGoogle Scholar
  9. 9.
    Gyermek L. 5-HT3 receptors: pharmacologie and therapeutic aspects. J Clin Pharmacol 1995; 35: 845–55PubMedGoogle Scholar
  10. 10.
    Blower P. A pharmacologie profile of oral granisetron. Semin Oncol 1995 Aug; 22 (4 Suppl. 10): 3–5PubMedGoogle Scholar
  11. 11.
    Sancillo LF, Pinkus LM, Jackson CB, et al. Emetic activity of zacopride in ferrets and its antagonism by pharmacological agents. Eur J Pharmacol 1990; 181: 303–6CrossRefGoogle Scholar
  12. 12.
    Van Wijngaarden I, Tulp MTM, Soudijn W. The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 1990; 188: 301–312PubMedCrossRefGoogle Scholar
  13. 13.
    Andrews PLR, Blower PR. The physiology of cytotoxic-induced emesis: new insights. Presented at a Satellite to the Seventh European Conference of Clinical Oncology Meeting; 1993 Nov; Jerusalem, 14–7Google Scholar
  14. 14.
    Andrews PLR, Bhandari P, Davey PT, et al. Are all 5-HT receptor antagonists the same? Eur J Cancer 1992; 28 Suppl. A: S2–6CrossRefGoogle Scholar
  15. 15.
    Lazarus HM, Bryson JC, Lemon E, et al. Antiemetic efficacy and pharmacokinetic analyses of the serotonin antagonist ondansetron (GR 38032F) during multiple-day chemotherapy with cisplatin prior to autologous bone marrow transplantation. J Natl Cancer Inst 1990; 82: 1776–8PubMedCrossRefGoogle Scholar
  16. 16.
    Addelman M, Erlichman C, Fine S, et al. Phase I/II trial of granisetron: a novel 5-hydroxytryptamine antagonist for the prevention of chemotherapy-induced nausea and vomiting. J Clin Oncol 1990; 8: 337–41PubMedGoogle Scholar
  17. 17.
    Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granisetron (BRL43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response. Cancer Chemother Pharmacol 1989; 24: 45–9PubMedCrossRefGoogle Scholar
  18. 18.
    Cassidy J, Raina V, Lewis C, et al. Pharmacokinetics and anti-emetic efficacy of BRL 43694, a new selective 5-HT3 antagonist. Br J Cancer 1988; 58: 651–3PubMedCrossRefGoogle Scholar
  19. 19.
    de Bruijn KM. Tropisetron: a review of the clinical experience. Drugs 1992; 43 Suppl. 3: 11–22PubMedCrossRefGoogle Scholar
  20. 20.
    Shah AK, Bhargava VO, Hahne WF, et al. Population pharmacokinetics and pharmacodynamics of metabolite after intravenous administration of dolasetron mesylate in patients receiving cisplatin chemotherapy [abstract]. Pharm Res 1995; 12 Suppl. 9: S360Google Scholar
  21. 21.
    Bonneterre J, Hecquet B, French Northern Oncology Group. Granisetron (IV) compared with ondansetron (IV plus oral) in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a cross-over study. Bull Cancer 1995 Dec; 82: 1038–43PubMedGoogle Scholar
  22. 22.
    Noble A, Bremer K, Goedhals L, et al. A double-blind, randomised, crossover comparison of granisetron and ondansetron in 5-day fractionated chemotherapy: assessment of efficacy, safety and patient preference. Eur J Cancer 1994; 30(8): 1083–8CrossRefGoogle Scholar
  23. 23.
    Navari R, Gandara D,Hesketh P, et al. Comparative clinical trial of granisetron and ondansetron in the prophylaxis of cisplatin-induced emesis. J Clin Oncol 1995 May; 13(5): 1242–8PubMedGoogle Scholar
  24. 24.
    Ruff P, Paska W, Goedhals L, et al. Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. Oncology 1994; 51: 113–8PubMedCrossRefGoogle Scholar
  25. 25.
    Stewart A, McQuade B, Cronje JDE, et al. Ondansetron compared with granisetron in the prophylaxis of cyclophosphamide-induced emesis in out-patients: a multicentre, double-blind, double dummy, randomised, parallel-group study. Oncology 1995; 52: 202–10PubMedCrossRefGoogle Scholar
  26. 26.
    Gebbia V, Cannata G, Testa A, et al. Ondansetron versus granisetron in the prevention of chemotherapy-induced nausea and vomiting. Cancer 1994 Oct; 74(7): 1945–52PubMedCrossRefGoogle Scholar
  27. 27.
    Martoni S, Angelelli B, Guaraldi M, et al. Granisetron (GRA) vs. ondansetron (OND) in the prevention of cisplatinum-induced emesis: an open randomized cross-over study [abstract]. Proc Am Soc Clin Oncol 1993; 13: 431Google Scholar
  28. 28.
    Leonardi V, Iannitto E, Meli M, et al. Ondansetron vs granisetron in the control of chemotherapy induced acute emesis: a multicentric randomized trial. Oncol Rep 1996; 3: 919–23PubMedGoogle Scholar
  29. 29.
    Italian Group for Antiemetic Research. Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 1995 Oct; 6: 805–10Google Scholar
  30. 30.
    Marty M, Kleisbauer J-P, Fournel P, et al. Is Navoban® (tropisetron) as effective as Zofran® (ondansetron) in cisplatin-induced emesis? Anti-Cancer Drugs 1995; 6 Suppl. 1: 15–21PubMedCrossRefGoogle Scholar
  31. 31.
    Jantunen IT, Kataja VV, Johansson RT. Ondansetron and tropisetron with dexamethasone in the prophylaxis of acute nausea and vomiting induced by non—cisplatin-containing chemotherapy. Acta Oncol 1992; 31(3): 573–5PubMedCrossRefGoogle Scholar
  32. 32.
    Campora E, Simoni C, Rosso R. Tropisetron verso ondansetron nella prevenzione e controllo dell’emesi in pazienti sottoposte a chemioterapia con FAC/FEC per carcinoma mammario metastatico o operato. Minerva Med 1994; 85: 25–31PubMedGoogle Scholar
  33. 33.
    Massidda B, Laconi S, Foddi MR, et al. Prevention of non-cisplatin induced emesis: role of the antagonists of 5-HT3 receptors [abstract]. Ann Oncol 1994; 5 Suppl. 8: 204Google Scholar
  34. 34.
    Mantovani A, Maccio L, Curreli L, et al. Comparison of the effectiveness of three 5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by highly emetogenic chemotherapy (high-dose cisplatin) for the treatment of primary head and neck cancer [abstract]. Proc Soc Am Clin Oncol 1994; 13: 428Google Scholar
  35. 35.
    Jantunen IT, Muhonen TT, Kataja VV, et al. 5-HT3 receptor antagonists in the prophylaxis of acute vomiting induced by moderately emetogenic chemotherapy — a randomised study. Eur J Cancer 1993; 29A: 1669–72PubMedCrossRefGoogle Scholar
  36. 36.
    Hesketh P, Navari R, Grote T, et al. Double-blind, randomised comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 1996 Aug; 14(8): 2242–9PubMedGoogle Scholar
  37. 37.
    Audhuy B, Cappelaere P, Martin M, et al. A double-blind, randomised comparison of the antiemetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy. Eur J Cancer 1996 May; 32A(5): 807–13PubMedGoogle Scholar
  38. 38.
    Lofters WS, Zee B. Dolasetron (DOL) vs ondansetron (OND) with and without dexamethasone (DEX) in the prevention of nausea (N) and vomiting (V) in patients (pts) receiving moderately emetogenic chemotherapy (MEC) [abstract]. Cancer Support Care 1995; 3: 339Google Scholar
  39. 39.
    Fauser AA, Duclos B, Chemaissani A, et al. Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. Eur J Cancer 1996 Aug; 32A(9): 1523–9PubMedCrossRefGoogle Scholar
  40. 40.
    Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 1997; 15: 103–9PubMedGoogle Scholar
  41. 41.
    Sullivan JR, Leyden MJ, Bell R. Decreased cisplatin-induced nausea and vomiting with chronic alcohol ingestion [letter]. N Engl J Med 1983; 309: 796PubMedGoogle Scholar
  42. 42.
    Triozzi P, Laszlo J. Optimum management of nausea and vomiting in cancer chemotherapy. Pract Ther Drugs 1987; 24: 136–49Google Scholar
  43. 43.
    Tonato M, Roila F. Methodology of antiemetic trials. Ann Oncol 1991; 2: 107–14PubMedCrossRefGoogle Scholar
  44. 44.
    Kris MG, Gralla RJ, Clark RA, et al. Incidence, course, and severity of delayed nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol 1985 Oct; 3(10): 1379–84PubMedGoogle Scholar
  45. 45.
    Fetting JH, Grochow LB, Folstein MF, et al. The course of nausea and vomiting after high-dose cyclophosphamide. Cancer Treat Rep 1982; 66: 1487–93PubMedGoogle Scholar
  46. 46.
    Morrow GR. Prevalence and correlates of anticipatory nausea and vomiting in chemotherapy patients. J Natl Cancer Inst 1982; 68: 585–8PubMedGoogle Scholar
  47. 47.
    Roila F, Ballatori E, De Angelis V. Dexamethasone, granisetron, or both for the prevention of nausea and vomiting during chemotherapy for cancer. N Engl J Med 1995 Jan; 332: 1–5CrossRefGoogle Scholar
  48. 48.
    Tonato M. Ondansetron plus dexamethasone: an effective combination in high-dose cisplatin therapy. Eur J Cancer 1991; 27 Suppl. 1: S12–4PubMedGoogle Scholar
  49. 49.
    Diehl V, Marty M. Efficacy and safety of antiemetics. Cancer Treat Rev 1994; 20: 379–92PubMedCrossRefGoogle Scholar
  50. 50.
    Lee CR, Plosker GL, McTavish D. Tropisetron: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993; 46: 925–43PubMedCrossRefGoogle Scholar
  51. 51.
    SmithKline Beecham Pharmaceuticals. Granisetron prescribing information. Philadelphia (PA), 1994Google Scholar
  52. 52.
    Glaxo Wellcome. Ondansetron prescribing information. Research Triangle Park (NC), 1995Google Scholar
  53. 53.
    Kris MG, Gralla RJ, Tyson LB, et al. Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 1989; 7: 208–14Google Scholar
  54. 54.
    Wilder-Smith OHG, Borgeat L, Chappuis P, et al. Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 1993; 72: 2239–41PubMedCrossRefGoogle Scholar
  55. 55.
    Gandara DR, Harvey WH, Monaghan GG, et al. The delayedemesis syndrome from cisplatin: phase III evaluation of ondansetron versus placebo. Semin Oncol 1992 Aug; 19 (4 Suppl. 10): 67–71PubMedGoogle Scholar
  56. 56.
    De Mulder PHM, Seynaeve C. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. Ann Intern Med 1990; 113: 834–40PubMedGoogle Scholar
  57. 57.
    Jantunen IT, Flander MK, Heikkenin MI, et al. Comparison of ondansetron with customary treatment in the prophylaxis of nausea and emesis induced by non-cisplatin containing chemotherapy. Acta Oncologica 1993; 32(4): 413–5PubMedCrossRefGoogle Scholar
  58. 58.
    Jones AL, Hill AS, Soukop M, et al. Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy. Lancet 1991; 338: 483–7PubMedCrossRefGoogle Scholar
  59. 59.
    Navari RM, Madajewica S, Anderson N, et al. Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo. J Clin Oncol 1995 Sep; 13(9): 2408–16PubMedGoogle Scholar
  60. 60.
    Rosso R, Campora E, Cetto G, et al. Oral ondansetron (GR 38032F) for the control of acute and delayed cyclophosphamide-induced emesis. Anticancer Res 1991; 11: 937–40PubMedGoogle Scholar
  61. 61.
    de Wit R, de Boer-Dennert M, Stoter G, et al. Sustainment of efficacy of tropisetron during 6 courses of cisplatin-containing chemotherapy [abstract]. Ann Oncol 1993; 3 Suppl. 5: 185Google Scholar
  62. 62.
    Sorbe BG, Hauogberg T, Glimelius B, et al. A randomized, multicenter study comparing the efficacy and tolerability of tropisetron, a new 5-HT3 receptor antagonist, with a metoclopramide-containing antiemetic cocktail. Cancer 1994 Jan; 73: 445–54PubMedCrossRefGoogle Scholar
  63. 63.
    Granisetron Study Group. Incidence of delayed cisplatin-induced emesis following acute antiemetic prophylaxis with granisetron. Presented at Advances in Emetic Control. 15th Union Against Cancer: 1990 Aug 17; HamburgGoogle Scholar
  64. 64.
    Heron JF, Goedhals L, Jordan JP, et al. Oral granisetron alone and in combination with dexamethasone: a double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. Ann Oncol 1995; 5: 579–84Google Scholar
  65. 65.
    Kris MG, Pisters KMW, Hinkley L. Delayed emesis following anticancer chemotherapy. Support Care Cancer 1994; 2: 297–300PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 1998

Authors and Affiliations

  1. 1.Department of Oncology and MedicineJohns Hopkins Oncology CenterBaltimoreUSA

Personalised recommendations