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Factors influencing the choice of 5-HT3-receptor antagonist antiemetics: focus on elderly cancer patients

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Abstract

With old age comes declining organ function, cognitive impairment, increased likelihood of comorbid conditions and multiple prescription and nonprescription pharmacotherapy. These issues are particularly relevant in elderly cancer patients, who commonly receive combination chemotherapy and supportive care agents along with radiation therapy and surgery. This situation can complicate medical care, particularly since over half of all cancers occur in those aged over 65 years. The 5-HT3-receptor antagonists as a class are highly effective antiemetics and are currently considered the gold standard for treatment of chemotherapy- and radiotherapy-induced nausea and vomiting. However, these agents do possess different pharmacologic properties, such as varying terminal half lives, routes of metabolism and selectivity for 5-HT3 receptors. These differences may have an impact on efficacy (e.g., duration of action of the drug) safety (e.g., the risk of drug interactions and potential adverse effects), and simplicity of the dosing regimen. The focus of this review is on some of the pertinent issues of 5-HT3 antagonists relating to elderly cancer patients.

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References

  1. Aapro MS (1993) Methodological issues in antiemetic studies. Invest New Drugs 11:243–253

    CAS  PubMed  Google Scholar 

  2. Aapro M, Bourke J (2003) Rapid intravenous administration of granisetron prior to chemotherapy is not arrhythmogenic: results of a pilot study. Eur J Cancer 39:927–931

    Article  CAS  PubMed  Google Scholar 

  3. Addelman M, Erlichman C, Fine S, Warr D, Murray C (1990) Phase I/II trial of granisetron: a novel 5-hydroxytryptamine antagonist for the prevention of chemotherapy-induced nausea and vomiting. J Clin Oncol 8:337–341

    CAS  PubMed  Google Scholar 

  4. Albertsen PC, Fryback DG, Storer BE, Kolon TF, Fine J (1995) Long-term survival among men with conservatively treated localized prostate cancer. JAMA 274:626–631

    Article  CAS  PubMed  Google Scholar 

  5. Albertsen PC, Fryback DG, Storer BE, Kolon TF, Fine J (1996) The impact of co-morbidity on life expectancy among men with localized prostate cancer. J Urol 156:127–132

    PubMed  Google Scholar 

  6. Algra A, Tijssen JGP, Roelandt JRTC, Pool J, Lubsen J (1991) QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation 83:1888–1894

    Google Scholar 

  7. Anonymous (2000) Cytochrome P450. http://www.anaesthetist.com/physiol/basics/metabol/cyp/cyp.htm

  8. Ashanani F, Heys SD, Eremin O (1999) The management of cancer in the elderly. J R Coll Surg Edinb 44:2–10

    PubMed  Google Scholar 

  9. Audhuy B, Cappelaere P, Marin M, et al (1996) A double-blind, randomised comparison of the antiemetic efficacy of two intravenous doses of dolasetron mesylate and granisetron in patients receiving high dose cisplatin chemotherapy. Eur J Cancer 32A:807–813

    Article  CAS  PubMed  Google Scholar 

  10. Aventis Pharmaceuticals (2000) Anzemet (dolasetron mesylate). Prescribing information

  11. Bertz RJ, Granneman GR (1997) Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 32:210–258

    Google Scholar 

  12. Bloomer JC, Baldwin SJ, Smith GJ, Ayrton AD, Clarke SE, Chenery RJ (1994) Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron. Br J Clin Pharmacol 38:557–566

    CAS  PubMed  Google Scholar 

  13. Blower P (1990) The role of specific 5-HT3 receptor antagonism in the control of cytostatic drug-induced emesis. Eur J Cancer 26 [Suppl 1]:S8–11

    Google Scholar 

  14. Blum RA, Majumdar A, McCrea J, et al (2003) Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects. Clin Ther 25:1407–1419

    Article  CAS  PubMed  Google Scholar 

  15. Boike SC, Ilson B, Zariffa N, Jorkasky DK (1997) Cardiovascular effects of i.v. granisetron at two administration rates and of ondansetron in healthy adults. Am J Health Syst Pharm 54:1172–1176

    CAS  Google Scholar 

  16. Boxenbaum H, Gillespie T, Heck K, Hahne W (1992) Human dolasetron pharmacokinetics: I. Disposition following single-dose intravenous administration to normal male subjects. Biopharm Drug Dispos 13:693–701

    Google Scholar 

  17. Cagnoni PJ, Matthes S, Day TC, Bearman SI, Shpall EJ, Jones RB (1999) Modification of the pharmacokinetics of high-dose cyclophosphamide and cisplatin by antiemetics. Bone Marrow Transplant 24:1–4

    Article  CAS  PubMed  Google Scholar 

  18. Carmichael J, Bergstrom B (2002) The cardiovascular safety of high-dose intravenous granisetron in cancer patients receiving highly emetogenic chemotherapy (abstract). 14th International Symposium of the Multinational Association of Supportive Care in Cancer (MASCC), 23–26 June 2002, Boston, MA

  19. Carmichael J, Cantwell BMJ, Edwards CM, et al (1989) A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with antiemetic response. Cancer Chemother Pharmacol 24:45–49

    CAS  PubMed  Google Scholar 

  20. Carmichael J, Philip PA, Forfar C, Harris AL (1995) An open study to assess the safety, tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease. Cancer Chemother Pharmacol 37:134–138

    Article  CAS  PubMed  Google Scholar 

  21. Catterson ML, Preskorn SH, Martin RL (1997) Pharmacodynamic and pharmacokinetic considerations in geriatric psychopharmacology. Geriatr Psychiatry 20:205–218

    CAS  Google Scholar 

  22. Coeburgh JWW (1996) Significant trends in cancer in the elderly. Eur J Cancer 32A:569–571

    Article  PubMed  Google Scholar 

  23. Cowan JD, Neidhart J, McClure S, et al (1991) Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst 83:1077–1084

    Google Scholar 

  24. Danjoux CE, Rider WD, Fitzpatrick PJ (1979) The acute radiation syndrome. A memorial to William Michael Court-Brown. Clin Radiol 30:581–588

    CAS  PubMed  Google Scholar 

  25. Davis MP, Homsi J (2001) The importance of cytochrome P450 monooxygenase CYP2D6 in palliative care. Support Care Cancer 9:442–451

    Google Scholar 

  26. Dixon CM, Colthup PV, Serabjit-Singh CJ, et al (1995) Multiple forms of cytochrome P450 are involved in the metabolism of ondansetron in humans. Drug Metab Dispos 23:1225–1230

    CAS  PubMed  Google Scholar 

  27. Doherty KM (1999) Closing the gap in prophylactic antiemetic therapy: patient factors in calculating the emetogenic potential of chemotherapy. Clin J Oncol Nurs 3:113–119

    CAS  PubMed  Google Scholar 

  28. Dretakis KE, Dretakis EK, Papakitsou EF, Psarakis S, Steriopoulos K (1998) Possible predisposing factors for the second hip fracture. Calcif Tissue Int 62:366–369

    Article  CAS  PubMed  Google Scholar 

  29. Eastell R, Reid DM, Compston J, et al (2001) Secondary prevention of osteoporosis—when should a non-vertebral fracture be a trigger for action? Q J Med 94:575–597

    Article  CAS  Google Scholar 

  30. Ewer MS, Benjamin RS (1997) Cardiac complications. In: Holland JF, Bast RC, Morton DL, et al (eds) Cancer medicine, 4th edn. Williams and Wilkins, Baltimore, pp 3197–215

  31. Extermann M (2002) Comorbidity and geriatric assessment in the elderly patient over the age of 70. Tumori 88 [Suppl 1]:S9

  32. Extermann M, Aapro M (2000) Assessment of the older cancer patient. Hematol Oncol Clin North Am 14:63–77

    CAS  PubMed  Google Scholar 

  33. Faulds D, Balfour JA, Chrisp P, Langtry HD (1991) Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs 41:400–449

    CAS  PubMed  Google Scholar 

  34. FDA (2003) Background information regarding EMEND(tm) (aprepitant) capsules. Gastrointestinal Drugs Advisory Committee, 6 March 2003, briefing Information. http://www.fda.gov/ohrms/dockets/ac/03/briefing/3928b1.htm

  35. Fukui H, Imai K, Chikaato M, Yamamoto M, Sato S (1991) Visceral afferent fibers and peripheral 5-HT3 receptor mediate cisplatin-induced emesis in dogs (abstract). Jpn J Pharmacol 55 [Suppl 1]:152P

  36. Gaedigk A (2000) Interethnic differences of drug-metabolizing enzymes. Int J Clin Pharmacol Ther 38:61–68

    CAS  PubMed  Google Scholar 

  37. Gilbert CJ, Petros WP, Vredenburgh J, et al (1998) Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer. Cancer Chemother Pharmacol 42:497–503

    Google Scholar 

  38. GlaxoSmithKline (1999) Zofran (ondansetron hydrochloride) tablets and Injection. Prescribing information

  39. Gralla RJ, Osoba D, Kris MG, et al (1999) Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 17:2971–2994

    CAS  PubMed  Google Scholar 

  40. Gridelli C, Perrone F, Gallo C, et al (2003) Chemotherapy for elderly patients with advanced non small cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study phase III randomized trial. J Natl Cancer Inst 95:362–372

    Article  CAS  PubMed  Google Scholar 

  41. Hesketh P, Navari R, Grote T, et al (1996) Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. Dolasetron Comparative Chemotherapy-induced Emesis Prevention Group. J Clin Oncol 14:2242–2249

    CAS  PubMed  Google Scholar 

  42. Higgins GA, Kilpatrick GJ, Bunce KT, Jones BJ, Tyers MB (1989) 5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret. Br J Pharmacol 97:247–255

    CAS  PubMed  Google Scholar 

  43. Hutchins LF, Unger JM, Crowley JJ, Coltman CA, Albain KS (1999) Underrepresentation of patients aged 65 years or older in cancer-treatment trials. N Engl J Med 341:2061–2067

    Article  CAS  PubMed  Google Scholar 

  44. Italian Group for Antiemetic Research (1995) Ondansetron versus granisetron, both combined with dexamethasone, in the prevention of cisplatin-induced emesis. Ann Oncol 6:805–810

    PubMed  Google Scholar 

  45. Jörgensen T, Johansson S, Kennerfalk A, Wallander M-A, Svärdsudd K. (2001) Prescription drug use, diagnoses, and healthcare utilization among the elderly. Ann Pharmacother 35:1004–1009

    Article  PubMed  Google Scholar 

  46. Kaiser R, Sezer O, Papies A, et al (2002) Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 20:2805–2811

    Article  CAS  PubMed  Google Scholar 

  47. Keefe DL (2000) Cardiovascular emergencies in the cancer patient. Semin Oncol 27:244–255

    CAS  PubMed  Google Scholar 

  48. Keefe DL (2002) The cardiotoxic potential of the 5-HT3 receptor antagonist antiemetics: is there cause for concern? Oncologist 7:65–72

    CAS  PubMed  Google Scholar 

  49. Kees F, Färber L, Bucher M, Mair G, Mörike K, Grobecker H (2001) Pharmacokinetics of therapeutic doses of tropisetron in healthy volunteers. Br J Clin Pharmacol 52:705–707

    Article  CAS  PubMed  Google Scholar 

  50. Kleisbauer J-P, García-Girón C, Antimi M, Azevedo MC, Blames H, Massuti-Sureda B, Contu A, Luque A, Pellier P (1998) Granisetron plus methylprednisolone for the control of high-dose cisplatin-induced emesis. Anticancer Drugs 9:387–332

    CAS  PubMed  Google Scholar 

  51. Koriech OM (1995) Fluoxetine treatment compromises the antiemetic efficacy of ondansetron in cancer patients. Clin Oncol 7:371–372

    CAS  Google Scholar 

  52. Kris MG, Cubeddu LX, Gralla RJ, et al (1996) Are more antiemetic trials with placebo necessary? Report of patient data from randomized trials of placebo antiemetics with cisplatin. Cancer 78:2193–2198

    Article  CAS  PubMed  Google Scholar 

  53. Laszlo J (1983) Emesis as limiting toxicity in cancer chemotherapy. In: Laszlo J (ed) Antiemetics and cancer chemotherapy. Williams and Wilkins, Baltimore London, pp 1–5

  54. Lindley CM, Hirsch JD, O’Neill CV, Transau MC, Gilbert CS, Osterhaus JT (1992) Quality of life consequences of chemotherapy-induced emesis. Qual Life Res 1:331–340

    CAS  PubMed  Google Scholar 

  55. Lorenz C, Eickhoff C, Bauman F, et al (2000) Does ondansetron affect the metabolism of cyclophosphamide? Int J Clin Pharmacol Ther 38:143–144

    Google Scholar 

  56. Love RR, Leventhal H, Easterling DV, Nerenz DR (1989) Side effects and emotional distress during cancer chemotherapy. Cancer 63:604–612

    CAS  PubMed  Google Scholar 

  57. Lowenthal RM, Eaton K (1996) Toxicity of chemotherapy. Hematol Oncol Clin North Am 10:967–990

    CAS  PubMed  Google Scholar 

  58. Marez D, Legrand M, Sabbagh N, et al (1997) Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 56 alleles, their frequencies and evolution. Pharmacogenetics 7:193–202

    CAS  PubMed  Google Scholar 

  59. Merck (2003) Emend, prescribing information. Merck and Company, Whitehouse Station, NJ

  60. Miller H, Mullaly K, Quigley J, Baran R, Coop AJ (2002) Use of 5-HT3 receptor antagonists in patients at risk of QTc prolongation: results of a retrospective claims based analysis (abstract P-364D). 37th American Society of Health System Pharmacists, 8–12 December, Atlanta, GA

  61. Minton NA (1994) Volunteer models for predicting antiemetic activity of 5-HT3-receptor antagonists. Br J Clin Pharmacol 37:525–530

    CAS  PubMed  Google Scholar 

  62. Monfardini S, Sorio R, Boes GH, Kaye S, Serraino D (1995) Entry and evaluation of elderly patients in European Organization for Research and Treatment of Cancer (EORTC) new-drug-development studies. Cancer 76:333–338

    CAS  PubMed  Google Scholar 

  63. Nelson DR, Thomas DR (1989) [3H]-BRL 43694 (granisetron), a specific ligand for 5-HT3 binding sites in rat brain cortical membranes. Biochem Pharmacol 38:1693–1695

    CAS  PubMed  Google Scholar 

  64. Newberry NR, Watkins CJ, Sprosen TS, Blackburn TP, Grahame-Smith DG, Leslie RA (1993) BRL 46470 potently antagonizes neural responses activated by 5-HT3 receptors. Neuropharmacology 32:729–735

    Google Scholar 

  65. Novartis Pharmaceuticals (1997) Navoban (tropisetron). Product information

  66. O’Brien BJ, Rusthoven J, Rocchi A, Latreille J, Fine S, Vandenberg T, Laberge F (1993) Impact of chemotherapy-associated nausea and vomiting on patients’ functional status and on costs: survey of five Canadian centres. Can Med Assoc J 149:296–302

    CAS  Google Scholar 

  67. Perez EA, Hesketh P, Sandbach J, et al (1998) Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study. J Clin Oncol 16:754–760

    CAS  PubMed  Google Scholar 

  68. Perez EA, Lembersky B, Kaywin P, Kalman L, Yocom K, Friedman C (1998) Comparable safety and antiemetic efficacy of a brief (30-second bolus) intravenous granisetron infusion and a standard (15-minute) intravenous ondansetron infusion in breast cancer patients receiving moderately emetogenic chemotherapy. Cancer J Sci Am 4:52–58

    CAS  PubMed  Google Scholar 

  69. Pignon J-P, Arriagada R, Ihde DC, et al (1992) A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327:1618–1624

    CAS  PubMed  Google Scholar 

  70. Ramamoorthy Y, Suh N, Tyndale RF, Sellers EM (2000) Differentially altered metabolism and inhibition of CYP2D6*10 (abstract). Clin Pharmacol Ther 67:121

    Google Scholar 

  71. Roche Laboratories (2000) Kytril (granisetron hydrochloride) tablets and injection. Prescribing information

  72. Roila F, Del Favero A (1995) Ondansetron clinical pharmacokinetics. Clin Pharmacokinet 29:95–109

    Google Scholar 

  73. Rowinsky EK, Donehower RC (1995) Paclitaxel (Taxol). N Engl J Med 332:1004–1014

    CAS  PubMed  Google Scholar 

  74. Ruff P, Paska W, Goedhals L, et al (1994) Ondansetron compared with granisetron in the prophylaxis of cisplatin-induced acute emesis: a multicentre double-blind, randomised, parallel-group study. Oncology 51:113–118

    CAS  PubMed  Google Scholar 

  75. Sanwald P, David M, Dow J (1996) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of dolasetron. Comparison with other indole-containing 5-HT3 antagonists. Drug Metab Dispos 24:602–609

    CAS  PubMed  Google Scholar 

  76. Satariano WA (1993) Aging, comorbidity, and breast cancer survival: an epidemiologic view. Adv Exp Med Biol 330:1–11

    CAS  PubMed  Google Scholar 

  77. Seidman A, Hudis C, Pierri MK, et al (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215–1221

    Article  CAS  PubMed  Google Scholar 

  78. Shah A, Lanman R, Bhargava V, Weir S, Hahne W (1995) Pharmacokinetics of dolasetron following single- and multiple-dose intravenous administration to normal male subjects. Biopharm Drug Dispos 16:177–189

    Google Scholar 

  79. Sheehy CM, Perry PA, Cromwell SL (1999) Dehydration: biological considerations, age-related changes, and risk factors in older adults. Biol Res Nurs 1:30–37

    CAS  PubMed  Google Scholar 

  80. Sparano JA (2002) Cardiac toxicity of trastuzumab (Herceptin): implications for the design of adjuvant trials. Semin Oncol 28 [Suppl 3]:20–27

    Google Scholar 

  81. Stanford BJ, Stanford SC (1999) Postoperative delirium indicating an adverse drug interaction involving the selective serotonin reuptake inhibitor, paroxetine? J Psychopharmacol 13:313–317

    CAS  PubMed  Google Scholar 

  82. Upward JW, Arnold BDC, Link C, Pierce DM, Allen A, Tasker TCG (1990) The clinical pharmacology of granisetron (BRL 43694), a novel specific 5-HT3 antagonist. Eur J Cancer 26 [Suppl 1]:S12–S15

  83. Van Wijngaarden I, Tulp MTM, Soudijn W (1990) The concept of selectivity in 5-HT receptor research. Eur J Pharmacol 188:301–312

    PubMed  Google Scholar 

  84. Wei JY (1995) Cardiovascular comorbidity in the older cancer patient. Semin Oncol 22 [Suppl 1]:9–10

    Google Scholar 

  85. Yancik R (1997) Cancer burden in the aged. An epidemiologic and demographic overview. Cancer 80:1273–1283

    Article  CAS  PubMed  Google Scholar 

  86. Yancik R, Ries LAG (2000) Aging and cancer in America. Hematol Oncol Clin North Am 14:17–23

    CAS  PubMed  Google Scholar 

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  1. Division of Medical Oncology, ’S.G. Moscati’ Hospital, Via Circumvallazione, 83100, Avellino, Italy

    Cesare Gridelli

  2. Clinique de Genolier, 1272, Genolier, Switzerland

    Matti Aapro

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  1. Cesare Gridelli
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  2. Matti Aapro
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Correspondence to Cesare Gridelli.

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Gridelli, C., Aapro, M. Factors influencing the choice of 5-HT3-receptor antagonist antiemetics: focus on elderly cancer patients. Support Care Cancer 12, 487–496 (2004). https://doi.org/10.1007/s00520-004-0596-3

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