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Antiemetics for Cancer Chemotherapy—Induced Nausea and Vomiting

A Review of Agents in Development

  • Section 1: Antiemetics in Oncology
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Abstract

Significant progress has been made in recent years in developing more effective means of preventing nausea and vomiting induced by cancer chemotherapy. With appropriate application of currently available antiemetic regimens, the majority of patients with cancer who are receiving chemotherapy can anticipate experiencing no emesis during their treatment. Nevertheless, incompletely controlled emesis remains a problem for a significant percentage of patients. Persistent challenges include delayed emesis and emesis following high-dose chemotherapy regimens. The goal of complete prevention of emesis in all patients remains elusive. Therefore, there is a strong rationale for investigating new antiemetic approaches.

New antiemetic agents currently under development target the neurotransmitters serotonin (5-hydroxytryptamine; 5-HT) and substance P. A number of new selective antagonists of serotonin 5-HT3 receptors are in clinical trials. Given the lack of clinically significant differences between the available 5-HT3 receptor antagonists, it appears unlikely that any of these new agents will have substantial advantages over currently approved agents. Several other serotonin receptors have been targeted including the 5-HT4, 5-HT1A and 5-HT2A receptors. Of these approaches, only agonism of the 5-HT1A receptor has produced an agent that has proceeded into clinical testing.

The most exciting new class of antiemetics currently under development focuses on antagonism of the effects of the neurotransmitter substance P. Results of early clinical trials with tachykinin neurokinin NK1 receptor antagonists demonstrate enhanced control of acute emesis with their addition to currently available agents and promising activity in controlling delayed emesis. Available evidence would strongly suggest that this class of agents will represent the next important advance in efforts to control nausea and vomiting induced by chemotherapy.

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References

  1. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993; 329 (24): 1790–6

    Article  PubMed  CAS  Google Scholar 

  2. 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; 3: 1379–84

    PubMed  CAS  Google Scholar 

  3. 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: 108–14

    PubMed  CAS  Google Scholar 

  4. Clark RA, Gralla RJ. Delayed emesis: a dilemma in antiemetic control. Support Care Cancer 1993; 1: 182–5

    Article  PubMed  CAS  Google Scholar 

  5. Kris MG, Pisters KMW, Hinkley L. Delayed emesis following anticancer chemotherapy. Support Care Cancer 1994; 2: 297–300

    Article  PubMed  CAS  Google Scholar 

  6. Tavorath R, Hesketh PJ. Drug treatment of chemotherapyinduced delayed emesis. Drugs 1996; 52: 639–48

    Article  PubMed  CAS  Google Scholar 

  7. Roila F. Control of acute cisplatin-induced emesis over repeat courses of chemotherapy. Oncology 1996; 53 Suppl. 1: 65–72

    Article  PubMed  CAS  Google Scholar 

  8. Frakes LA, Brehm TL, Kosty MP, et al. An all oral antiemetic regimen for patients undergoing high-dose chemotherapy with peripheral blood stem transplant. Bone Marrow Transplant 1997; 20: 473–8

    Article  PubMed  CAS  Google Scholar 

  9. Gralla RJ, Tyson LB, Kris MG, et al. The management of chemotherapy-induced nausea and vomiting. Med Clin North Am 1987; 71: 289–301

    PubMed  CAS  Google Scholar 

  10. Gralla RJ. Controlling emesis in patients receiving cancer chemotherapy. Recent Results Cancer Res 1991; 121: 68–85

    Article  PubMed  CAS  Google Scholar 

  11. Perez EA. Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol 1995; 13: 1036–43

    PubMed  CAS  Google Scholar 

  12. Morrow GR, Hickok JT, Rosenthal SN. Progress in reducing nausea and emesis: comparisons of ondansetron (Zofran), granisetron (Kytril) and tropisetron (Navoban). Cancer 1995; 76: 343–57

    Article  PubMed  CAS  Google Scholar 

  13. Beppu T, Ogawa M, Yamanaka T, et al. Clinical evaluation of azasetron hydrochloride: a new selective 5-HT3 receptor antagonist — antiemetic profile and plasma concentration in transcatheter arterial chemoembolization using CDDP for unresectable hepatocellular carcinoma. Gan To Kagaku Ryoho 1998; 25: 1197–202

    PubMed  CAS  Google Scholar 

  14. Tsukagoshi S. A new antiemetic ramosetron hydrochloride. Gan To Kagaku Ryoho 1997; 24: 371–80

    PubMed  CAS  Google Scholar 

  15. Grunberg SM, Akerley WL, Krailo MD, et al. Comparison of metoclopramide and metoclopramide plus dexamethasone for complete protection from cisplatinum-induced emesis. Cancer Invest 1986; 4: 379–85

    Article  PubMed  CAS  Google Scholar 

  16. Kris MG, Gralla RJ, Clark RA, et al. Antiemetic control and prevention of side effects of anticancer therapy with lorazepam or diphenhydramine when used in combination with metoclopramide plus dexamethasone. Cancer 1987; 60: 2816–22

    Article  PubMed  CAS  Google Scholar 

  17. Roila F, Tonato M, Cognetti F, et al. Prevention of cisplatininduced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9: 675–8

    PubMed  CAS  Google Scholar 

  18. Smith DB, Newlands ES, Rustin GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy. Lancet 1991; 338: 487–90

    Article  PubMed  CAS  Google Scholar 

  19. Hesketh PJ, Harvey WH, Beck TM, et al. Arandomized, doubleblind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol 1994; 12: 596–600

    PubMed  CAS  Google Scholar 

  20. Carmichael J, Bessel ES, Harris AL, et al. Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis. Br J Cancer 1994; 70: 1161–4

    Article  PubMed  CAS  Google Scholar 

  21. Sorbe B, Högberg T, Himmelmann A, et al. Efficacy and tolerability of tropisetron in comparison with a combination of tropisetron and dexamethasone in the control of nausea and vomiting induced by cisplatin-containing chemotherapy. Eur J Cancer 1994; 30A: 629–34

    Article  PubMed  CAS  Google Scholar 

  22. Italian Group for Antiemetic Research. Dexamethasone, granisetron or both for the prevention of nausea and vomiting during chemotherapy for cancer. N Engl J Med 1995; 332: 1–5

    Article  Google Scholar 

  23. Bregni M, Siena S, Di Nicola M, et al. Tropisetron plus haloperidol to ameliorate nausea and vomiting associated with highdose alkylating agent cancer chemotherapy. Eur J Cancer 1991; 27: 561–5

    Article  PubMed  CAS  Google Scholar 

  24. Herrstedt J, Sigsgaard T, Boesgaard M, et al. Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy. N Engl J Med 1994; 328: 1076–80

    Article  Google Scholar 

  25. Herrstedt J, Sigsgaard T, Handberg J, et al. Randomized, doubleblind comparison of ondansetron vs ondansetron plus metopimazine as antiemetic prophylaxis during platinumbased chemotherapy in patients with cancer. J Clin Oncol 1997; 15: 1690–6

    PubMed  CAS  Google Scholar 

  26. Hesketh PJ. Treatment of chemotherapy-induced emesis in the 1990s: impact of the 5-HT3 receptor antagonists. Support Care Cancer 1994; 2: 286–92

    Article  PubMed  CAS  Google Scholar 

  27. Roila F, Bracarda S, Tonato M, et al. Ondansetron (GR38032) in the prophylaxis of acute and delayed cisplatin-induced emesis. Clin Oncol (R Coll Radiol) 1990; 2: 268–72

    Article  CAS  Google Scholar 

  28. Hesketh PJ. Management of cisplatin-induced delayed emesis. Oncology 1996; 53: Suppl. 1: 73–7

    Article  PubMed  CAS  Google Scholar 

  29. Italian Group for Antiemetic Research. Ondansetron versus metoclopramide, both combined with dexamethasone, in the prevention of cisplatin-induced delayed emesis. J Clin Oncol 1997; 15: 124–30

    Google Scholar 

  30. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst 1991; 83: 613–20

    Article  PubMed  CAS  Google Scholar 

  31. Goldschmidt H, Salwender H, Gerlinde E, et al. Comparison of oral itasetron with oral ondansetron: results of a double-blind, active-controlled phase II study in chemotherapy-naive patients receiving moderately emetogenic chemotherapy. Anticancer Drugs 1997; 8: 436–44

    Article  PubMed  CAS  Google Scholar 

  32. Gomez-de-Segura IA, Grande AG, De Miguel E. Antiemetic effects of Lerisetron in radiation-induced emesis in the dog. Acta Oncol 1998; 37 (7–8): 759–63

    PubMed  CAS  Google Scholar 

  33. Tang J, D’Angelo R, White PF, et al. The efficacy of RS-25259, a long-acting selective 5-HT3 receptor antagonist, for preventing postoperative nausea and vomiting after hysterectomy procedures. Anesth Analg 1998; 87: 462–7

    PubMed  CAS  Google Scholar 

  34. Minami M, Endo T, Tamakai H, et al. Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets. Eur J Pharmacol 1997; 321: 333–42

    Article  PubMed  CAS  Google Scholar 

  35. Baxter GS, Clarke DE. Benzimidazolone derivatives act as 5-HT4 receptor ligands in rat oesophagus. Eur J Pharmacol 1992; 212 (2–3): 225–9

    Article  PubMed  CAS  Google Scholar 

  36. Herrstedt J. Antiemetic research: a look to the future. Support Care Cancer 1998; 6: 8–12

    Article  PubMed  CAS  Google Scholar 

  37. Lucot J, Crampton G. 8-OH-DPAT suppresses vomiting in the cat elicited by motion, cisplatin or xylazine. Pharmacol Biochem Behav 1989; 33: 627–31

    Article  PubMed  CAS  Google Scholar 

  38. Okada F, Torii Y, Saito H, et al. Antiemetic effects of serotonergic 5-HT1a-receptor agonists in Suncus murinus. Jpn J Pharmacol 1994; 64: 109–14

    Article  PubMed  CAS  Google Scholar 

  39. Foreman MM, Fuller RW, Leander JD, et al. Preclinical studies on LY 228729: a potent and selective serotonin1A agonist. J Pharmacol Exp Ther 1993; 267: 58–71

    PubMed  CAS  Google Scholar 

  40. Wolff MC, Leander JD. Antiemetic effects of 5-HT1A agonists in the pigeon. Pharmacol Biochem Behav 1994; 49: 385–91

    Article  PubMed  CAS  Google Scholar 

  41. Wolff MC, Leander JD. Comparison of the antiemetic effects of a 5-HT1A agonist, LY228729, and 5-HT3 antagonists in the pigeon. Pharmacol Biochem Behav 1995; 52: 571–5

    Article  PubMed  CAS  Google Scholar 

  42. Alfieri AB, Cubeddu LX. Comparative efficacy of a single oral dose of ondansetron and of buspirone against cisplatin-induced emesis in cancer patients. Br J Cancer 1995; 72: 1013–5

    Article  PubMed  CAS  Google Scholar 

  43. Okada F, Saito H, Matsuki N. Blockade of motion- and cisplatininduced emesis by a 5-HT2 receptor agonist in Suncus murinus. Br J Pharmacol 1995; 114: 931–4

    Article  PubMed  CAS  Google Scholar 

  44. Tonini M, Candura SM, Messori E, et al. Therapeutic potential of drugs with mixed 5-HT4/5-HT3 antagonist action in the control of emesis. Pharmacol Res 1995; 31: 257–60

    Article  PubMed  CAS  Google Scholar 

  45. Pizzo BA, Pisters KM, Miller VA, et al. Oral cisapride for the control of delayed vomiting following high-dose cisplatin. Support Care Cancer 1999; 7: 44–6

    Article  PubMed  CAS  Google Scholar 

  46. Von Euler VS, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol (Lond) 1931; 72: 577–83

    Google Scholar 

  47. Chang M, Leeman SE. Isolation of sialogogic peptide from bovine hypothalamic tissue and its characterization as substance P. J Biol Chem 1970; 245: 4784–90

    PubMed  CAS  Google Scholar 

  48. Watson JW, Nagahisa A, Lucot JB, et al. The tachykinins and emesis: towards complete control. In: Reynolds DJM, Andrews PLR, Davis CJ, editors. Serotonin and the scientific basis of anti-emetic therapy. Oxford: Oxford Clinical Communications, 1995: 233–8

    Google Scholar 

  49. Gardner CJ, Bountra C, Bunce KT, et al. Anti-emetic activity of neurokinin NK1 receptor antagonists is mediated centrally in the ferret [abstract]. Br J Pharmacol 1994; 112 Suppl.: 516P

    Google Scholar 

  50. Tattersall FD, Rycroft W, Francis B, et al. Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agents cisplatin in ferrets. Neuropharmacology 1996; 35: 1121–9

    Article  PubMed  CAS  Google Scholar 

  51. Rudd JA, Jordan CC, Naylor RJ. The action of the NK1 tachykinin receptor antagonist CP-99,994 in antagonizing the acute and delayed emesis induced by cisplatin in the ferret. Br J Pharmacol 1996; 119: 931–6

    Article  PubMed  CAS  Google Scholar 

  52. Beattie DT, Beresford IJM, Connor HE, et al. The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist. Br J Pharmacol 1995; 116: 3149–53

    Article  PubMed  CAS  Google Scholar 

  53. Saito R, Suehiro Y, Ariumi H, et al. Anti-emetic effects of a novel NK1 receptor antagonist HSP-117 in ferrets. Neurosci Lett 1998; 254: 169–72

    Article  PubMed  CAS  Google Scholar 

  54. Singh L, Field MJ, Hughs J, et al. The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emsis in the ferret. Eur J Pharmacol 1997; 321: 209–16

    Article  PubMed  CAS  Google Scholar 

  55. Bountra C, Buncek K, Dale T, et al. Anti-emetic profile of a non-peptide neurokinin NK1 receptor antagonist CP-99,994 in ferrets. Eur J Pharmacol 1993; 249: R3–R4

    Article  PubMed  CAS  Google Scholar 

  56. Watson JW, Gonsalves SF, Fossa AA, et al. The antiemetic effect of CP-99,994 in the ferret and the dog: role of the NK1 receptor. Br J Pharmacol 1995; 115: 84–94

    Article  PubMed  CAS  Google Scholar 

  57. Tattersall FD, Rycroft W, Hill RG, et al. Enantioselective inhibition of apomorphine-induced emesis in the ferret by the neurokinin1 receptor antagonist CP-99,994. Neuropharmacology 1994; 33: 259–60

    Article  PubMed  CAS  Google Scholar 

  58. Lucot JB, Obach RS, McLean S, et al. The effect of CP-99994 on the responses to provocative motion in the cat. Br J Pharmacol 1997; 120: 116–20

    Article  PubMed  CAS  Google Scholar 

  59. Gardener C, Perren M. Inhibition of anaesthetic-induced emesis by an NK1 of 5-HT3 receptor antagonist in the house musk shrew, Suncus murinus. Neuropharmacology 1998; 37: 1643–4

    Article  Google Scholar 

  60. Rudd JA, Ngan MP, Wai MK. Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew). European J Pharmacol 1999; 366: 243–52

    Article  CAS  Google Scholar 

  61. Grelot L, Dapzol J, Esteve E, et al. Potent inhibition of both the acute and delayed emetic responses to cisplatin in piglets treated with GR205171, a novel highly selective tachykinin NK1 receptor antagonist. Br J Pharmacol 1998; 124: 1643–50

    Article  PubMed  CAS  Google Scholar 

  62. Kris MG, Radford J, Pizzo BA, et al. Control of emesis following cisplatin by CP-122,721, a selective NK1 receptor antagonist. J Natl Cancer Inst 1997; 89: 817–8

    Article  PubMed  CAS  Google Scholar 

  63. Van Belle S, Cocquyt V, De Smet M, et al. Comparison of a neurokinin-1 antagonist, L-758,298, to ondansetron in the prevention of cisplatin-induced emesis [abstract no. 198]. Proc Am Soc Clin Oncol 1998; 17: 51a

    Google Scholar 

  64. Hesketh PJ, Gralla RJ, Webb RT, et al. Randomized phase II study of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis. J Clin Oncol 1999; 17: 338–43

    PubMed  CAS  Google Scholar 

  65. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med 1999; 340: 190–5

    Article  PubMed  CAS  Google Scholar 

  66. Van Belle S, Reinhardt R, Lichinitser M, et al. Prevention of cisplatin-induced emesis by the selective neurokinin-1 antagonist, L-754, 030, and its prodrug, L-758, 298 [abstract no. 2281]. Proc Am Soc Clin Oncol 1999; 18: 590a

    Google Scholar 

  67. Fumoleau P, Graham E, Giovanni M, et al. Control of acute cisplatin-induced emesis and nausea with the NK1 receptor antagonist, GR205171, in combination with ondansetron [abstract no. 225]. Proc Am Soc Clin Oncol 1998; 17: 58a

    Google Scholar 

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Correspondence to Paul J. Hesketh.

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Rizk, A.N., Hesketh, P.J. Antiemetics for Cancer Chemotherapy—Induced Nausea and Vomiting. Drugs R&D 2, 229–235 (1999). https://doi.org/10.2165/00126839-199902040-00001

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