Pharmaceutisch Weekblad

, Volume 10, Issue 6, pp 237–245 | Cite as

Continuous infusion of low-dose doxorubicin, epirubicin and mitoxantrone in cancer chemotherapy: A review

  • Janke Greidanus
  • Pax H. B. Willemse
  • Donald R. A. Uges
  • Evrard T. H. G. J. Oremus
  • Zacharias J. de Langen
  • Elisabeth G. E. de Vries
Review Articles


With the recent development of reliable portable pumps and safe venous access systems, continuous infusion of chemotherapeutic agents on an out-patient basis has become feasible. Advantages of continuous infusion are the long-term exposure of tumour cells to the drug and the fact that most toxic effects are reduced for doxorubicin, epirubicin and mitoxantrone due to elimination of the high peak plasma levels. Preliminary data for doxorubicin suggest that its antitumour activity is maintained. Pharmacokinetic studies with epirubicin and mitoxantrone showed a linear relationship between drug dose infused and the steady-state plasma level for these drugs. The area under the curve for leukocytes drug level was higher during continuous infusion than after an equitoxic bolus injection of epirubicin and mitoxantrone. Well-randomized clinical trials will be necessary to investigate the role of continuous infusion of antracyclines and mitoxantrone in cancer chemotherapy in the future.


Clinical trials Doxorubicin Epirubicin Infusions, continuous Mitoxantrone Pharmacokinetics Toxicology 


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  1. 1.
    Bothe A, Daly J. Technical aspects of vascular access for infusional chemotherapy. In: Lokich JJ, ed. Cancer chemotherapy by infusion. Chicago: Precept Press Inc., 1987:59–73.Google Scholar
  2. 2.
    Carlson RW, Sikic BI. Continuous infusion or bolus injection in cancer chemotherapy. Ann Intern Med 1983;99:823–33.PubMedGoogle Scholar
  3. 3.
    Vogelzang NJ. Continuous infusion chemotherapy. J Clin Oncol 1984;2:1289–304.PubMedGoogle Scholar
  4. 4.
    Lokich JJ. Cancer chemotherapy by constant infusion. Hosp Pract 1983;18:500–9.Google Scholar
  5. 5.
    Lokich J, Bothe A, Zipoli T, et al. Constant infusion schedule for adriamycin: a phase I–II clinical trial of a 30-day schedule by ambulatory pump delivery system. J Clin Oncol 1983;1:24–8.PubMedGoogle Scholar
  6. 6.
    Garnick MB, Weiss GR, Steele GD, et al. Clinical evaluation of long-term, continuous infusion doxorubicin. Cancer Treat Rep 1983;67:133–42.PubMedGoogle Scholar
  7. 7.
    Smith IE. Optimal schedule for anthracyclines. Eur J Cancer Clin Oncol 1985;21:159–61.PubMedGoogle Scholar
  8. 8.
    Legha SS, Benjamin RS, Mackay B, et al. Adriamycin therapy by continuous intravenous infusion in patients with metastatic breast cancer. Cancer 1982;49:1762–6.PubMedGoogle Scholar
  9. 9.
    Legha SS, Benjamin RS, Mackay B, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982;96:133–9.PubMedGoogle Scholar
  10. 10.
    Sikic BI, Collins JM, Mimnaugh EG, Gram TE. Improved therapeutic index of bleomycin when administered by continuous infusion in mice. Cancer Treat Rep 1978;62:2011–7.PubMedGoogle Scholar
  11. 11.
    Peng YM, Alberts DS, Chen H-SG, Mason N, Moon TE. Antitumour activity and plasma kinetics of bleomycin by continuous and intermittent administration. Br J Cancer 1980;41:644–7.PubMedGoogle Scholar
  12. 12.
    Lokich JJ. Phase I study ofcis-diamminedichloroplatinum(II) administered as a constant five-day infusion. Cancer Treat Rep 1980;64:905–8.PubMedGoogle Scholar
  13. 13.
    Lokich J, Bothe A Jr, Fine N, Perri J. Phase I study of protracted venous infusion of 5-fluorouracil. Cancer 1981;48:2565–8.PubMedGoogle Scholar
  14. 14.
    Baserga R. The cell cycle. N Engl J Med 1981;304:453–9.PubMedGoogle Scholar
  15. 15.
    Pardee AB. Principles of cancer biology, biochemistry and cell biology. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology. Philadelphia: J.B. Lippincott, 1985:3–22.Google Scholar
  16. 16.
    Shackney SE, Ritch PS. Cell kinetics. In: Chabner BA, ed. Pharmacological principles of cancer treatment. Philadelphia: W.B. Saunders, 1982:45–76.Google Scholar
  17. 17.
    Lokich JJ. Introduction to the concept and practice of infusion chemotherapy. In: Lokich JJ, ed. Cancer chemotherapy by infusion. Chicago: Precept Press Inc., 1987:3–11.Google Scholar
  18. 18.
    Shimoyama M. Cytocidal action of anticancer agents: evaluation of the sensitivity of cultured animal and human cancer cells. Bibl Haematologica 1975;40:711–22.Google Scholar
  19. 19.
    Chlebowski RT, Paroly WI, Pugh RP, et al. Adriamycin given as a weekly schedule without a loading dose: clinically effective with reduced incidence of cardiac toxicity. Cancer Treat Rep 1980;64:47–51.PubMedGoogle Scholar
  20. 20.
    Cooper KR, Hong WK. Prospective study of the pulmonary toxicity of continuously infused bleomycin. Cancer Treat Rep 1981;65:419–25.PubMedGoogle Scholar
  21. 21.
    Lokich JJ. Colorectal cancer. In: Lokich JJ, ed. Cancer chemotherapy by infusion. Chicago: Precept Press Inc., 1987:291–303.Google Scholar
  22. 22.
    Curt GA, Clendeninn NJ, Chabner BA. Drug resistance in cancer. Cancer Treat Rep 1984;68:87–99.PubMedGoogle Scholar
  23. 23.
    Zijlstra JG, De Vries EGE, Mulder NH. Multifactorial drug resistance in an adriamycin resistant human small cell lung carcinoma cell line. Cancer Res 1987;47:1780–4.PubMedGoogle Scholar
  24. 24.
    DiMarco A, Gaetani M, Scarpinato G. Adriamycin: a new antibiotic with antitumor activity. Cancer Chemother Rep 1969;53:33–7.PubMedGoogle Scholar
  25. 25.
    Young RS, Ozols RF, Myers CE. The anthracycline antineoplastic drugs. N Engl J Med 1981;305:139–53.PubMedGoogle Scholar
  26. 26.
    Weiss RB, Sarosy G, Clagett-Carr K, Russo M, Leyland-Jones B. Anthracycline analogs: the past, present and future. Cancer Chemother Pharmacol 1986;18:185–97.PubMedGoogle Scholar
  27. 27.
    Chabner BA, Myers LE. Clinical pharmacology of cancer chemotherapy: Antitumor antibiotics. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer principles and practice of oncology. Philadelphia: J.B. Lippincott, 1985:310–5.Google Scholar
  28. 28.
    Krishan A, Frei E. Effect of adriamycin on the cell cycle traverse and kinetics of cultured human lymphoblasts. Cancer Res 1976;36:143–50.PubMedGoogle Scholar
  29. 29.
    Benjamin RS, Riggs CF, Bachur NR. Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther 1973:14:592–600.PubMedGoogle Scholar
  30. 30.
    Benjamin RS, Wiernik PH, Bachur NR. Adriamycin chemotherapy — efficacy, safety and pharmacologic basis of an intermittent single high dosage schedule. Cancer 1974;33:19–27.PubMedGoogle Scholar
  31. 31.
    Legha SS, Hortobagyi GN, Benjamin RS. Anthracyclines. In: Lokich JJ, ed. Cancer chemotherapy by infusion. Chicago: Precept Press Inc., 1987:130–44.Google Scholar
  32. 32.
    Torti FM, Bristow MR, Howes AE, et al. Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Ann Intern Med 1983;99:745–9.PubMedGoogle Scholar
  33. 33.
    Ritch PS, Occhipinti SJ, Skramstad KS, Shackney SE. Increased relative effectiveness of doxorubicin against slowly proliferating sarcoma 180 cells after prolonged drug exposure. Cancer Treat Rep 1982;66:1159–68.PubMedGoogle Scholar
  34. 34.
    Pacciarini MA, Barbieri B, Colombo T, Broggini M, Garattini S, Dorelli MG. Distribution and antitumor effectivity of adriamycin given in a high-dose and a repeated low-dose schedule to mice. Cancer Treat Rep 1978;62:791–800.PubMedGoogle Scholar
  35. 35.
    Tormey DC. Adriamycin in breast cancer. An overview of studies. Cancer Treat Rep 1975;6:319–27.Google Scholar
  36. 36.
    Frederiksen PL, Joergensen ST, Roesdahl K, Thomson J, Mourdsen HT. Activity of adriamycin in metastatic breast cancer resistant to a combination regimen with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine and prednisone. Cancer Treat Rep 1978;62:449–50.PubMedGoogle Scholar
  37. 37.
    Bonadonna G, ed. Advances in anthracycline chemotherapy: epirubicin. Milano: Masson Italia, 1984.Google Scholar
  38. 38.
    Young CW, Raymond V. Clinical assessment of the structure-activity relationship of anthracyclines and related synthetic derivatives. Cancer Treat Rep 1986; 70:51–63.PubMedGoogle Scholar
  39. 39.
    Ganzina F. 4-Epi-doxorubicin, a new analogue of doxorubicin: a preliminary overview of preclinical and clinical data. Cancer Treat Rev 1983;10:1–22.Google Scholar
  40. 40.
    Mourdsen HT, Bastholt L, Somers R, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC soft tissue and bone sarcoma group. Eur J Clin Oncol 1987;23:1477–83.Google Scholar
  41. 41.
    Jain KK, Casper ES, Geller NL, et al. A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 1983;3:818–26.Google Scholar
  42. 42.
    Weenen H, Lankelma J, Penders PGM, et al. Pharmacokinetics of 4′-epidoxorubicin in man. Invest N Drugs 1983;1:59–64.Google Scholar
  43. 43.
    Weenen H, Van Maanen JMS, De Planque MM, McVie JG, Pinedo HM. Metabolism of 4′-modified analogs of doxorubicin. Unique glucuronidation pathway for 4′-epidoxorubicin. Eur J Cancer Clin Oncol 1984;20:919–26.PubMedGoogle Scholar
  44. 44.
    Jones WG, Mattson W. Phase II study of weekly low dose 4′-epidoxorubicin in advanced postmenopausal breast cancer. Cancer Treat Rep 1984;68:675–7.PubMedGoogle Scholar
  45. 45.
    De Vries EGE, Greidanus J, Mulder NH, Nieweg MB, et al. A phase I and pharmacokinetic study with 21-day continuous infusion of epirubicin. J Clin Oncol 1987;5:1445–51.PubMedGoogle Scholar
  46. 46.
    Greidanus J, Willemse PHB, Sleijfer DTh, et al. Phase II study of a 21-days continuous infusion schedule with epirubicin in metastatic colorectal cancer. Eur J Cancer Clin Oncol 1988;24:801–2.PubMedGoogle Scholar
  47. 47.
    Holdener EE, Hansen HE, Host H, et al. Epirubicin in colorectal cancer. Invest N Drugs 1985;3:63–6.Google Scholar
  48. 48.
    Arjani JA, Kanojia MD, Bodey GP. Phase II evaluation of epirubicin in patients with metastatic colorectal carcinoma. Cancer Treat Rep 1984;68:1507–8.PubMedGoogle Scholar
  49. 49.
    Wadler S, Green M, Muggia F. The role of anthracyclines in the treatment of gastric cancer. Cancer Treat Rev 1985;12:105–32.PubMedGoogle Scholar
  50. 50.
    Schenkenberg TD, Von Hoff DD. Mitoxantrone: a new anticancer drug with significant clinical activity. Ann Intern Med 1986;105:67–81.PubMedGoogle Scholar
  51. 51.
    Smith IE. Mitoxantrone (novantrone): a review of experimental and early clinical studies. Cancer Treat Rev 1983;10:103–15.Google Scholar
  52. 52.
    Posner LE, Duhart G, Goldberg J, Bernstein T, Cartwright K. Mitoxantrone: an overview of safety and toxicity. Invest N Drugs 1985;3:123–32.Google Scholar
  53. 53.
    Anderson KC, Garnick MB, Meshad MW, et al. Phase I trial of mitoxantrone by 24-hour continuous infusion. Cancer Treat Rep 1983;67:435–8.PubMedGoogle Scholar
  54. 54.
    Rowland CG, Sewell G. Optimal drug delivery: a phase I study of continuously infused mitoxantrone. Proc ECCO 1987;4:abstract no 441.Google Scholar
  55. 55.
    World Health Organization. Handbook for reporting result of cancer treatment. WHO Offset Publication no 48. 's-Gravenhage: Nijhoff, 1979.Google Scholar
  56. 56.
    De Vries EGE, Greidanus J, Mulder NH, et al. A phase I and pharmacokinetic study with 21-day continuous infusion of mitoxantrone [Abstract]. Proc ASCO 1988;7:no.218.Google Scholar
  57. 57.
    Greenblatt DJ, Koch-Weser J. Drug therapy. Clinical pharmacokinetics part I. N Engl J Med 1975;293:702–5.PubMedGoogle Scholar
  58. 58.
    Greenblatt DJ, Koch-Weser J. Drug therapy. Clinical pharmacokinetics part II. N Engl J Med 1975;293:964–70.PubMedGoogle Scholar
  59. 59.
    Oosterbaan MJM, Dirks MJM, Vree TB, et al. Clinical pharmacokinetics of adriamycin. J Drug Res 1982;7:1372–8.Google Scholar
  60. 60.
    Dalton WS, Alberts DS. Pharmacokinetics of mitoxantrone. In: Henning T, Mouridsen PhD, Zalmen A, eds. Pharmanual, the role of mitoxantrone in malignant diseases. New Jersey: Pharmalibri Publishers, 1987:5–18.Google Scholar
  61. 61.
    Robert J, Vrignaud P, Nguyen-Ngog T, et al. Comparative pharmacokinetics and metabolism of doxorubicin and epirubucin in patients with metastatic breast cancer. Cancer Treat Rep 1985;69:633–40.PubMedGoogle Scholar
  62. 62.
    Camaggi CM, Strocchi E, Comparsi R, et al. Biliairy excretion and pharmacokinetics of 4′-epidoxorubicin (epirubicin) in advanced cancer patients. Cancer Chemother Pharmacol 1986;18:47–50.PubMedGoogle Scholar
  63. 63.
    Sinkule JA, Vogelzang NJ, Clinical pharmacokinetics of continuous doxorubicin infusion using an implanted drug administration device [Abstract]. Proc AACR 1985;26:217.Google Scholar
  64. 64.
    Strum S, McDermed J, Korn A, Joseph C. Improved methods for venous access: the port-a-cath, a totally implanted catheter system. J Clin Oncol 1986;4:596–603.PubMedGoogle Scholar
  65. 65.
    Brincker H, Saeter G. Fifty-five patient years' experience with a totally implanted system for intravenous chemotherapy. Cancer 1986;57:1124–9.PubMedGoogle Scholar
  66. 66.
    Reed WP, Newman KA, Applefeld MM, Sutton FJ. Drug extravasation as a complication of venous access ports. Ann Intern Med 1985;102:788–90.PubMedGoogle Scholar
  67. 67.
    Greidanus J, De Vries EGE, Nieweg MB, et al. Evaluation of a totally implanted venous access port and portable pump in a continuous chemotherapy infusion schedule on an outpatient basis. Eur J Cancer Clin Oncol 1987;23:1653–7.PubMedGoogle Scholar
  68. 68.
    Lokich JJ, Bothe A, Benotti P, Moore C. Complications and management of implanted venous access catheters. J Clin Oncol 1985;3:710–7.PubMedGoogle Scholar
  69. 69.
    Lokich JJ, Bothe A, Fini N, Perri J. The delivery of cancer chemotherapy by constant venous infusion. Cancer 1982;50:2731–5.PubMedGoogle Scholar
  70. 70.
    Lokich JJ, Becker B, Subclavian vein thrombosis in patients treated with infusion chemotherapy for advanced malignancy. Cancer 1983;52:1586–9.PubMedGoogle Scholar
  71. 71.
    Tucker EM. Drug administration system for infusion chemotherapy. In: Lokich JJ, ed. Cancer chemotherapy by infusion. Chicago: Precept Press Inc., 1987:41–58.Google Scholar
  72. 72.
    Vogelzang NJ, Ruane M, Ratain MJ, Dhowlatshahi K, Chodak GW. A programmable and implantable pumping system for systemic chemotherapy: a performance analysis in 52 patients. J Clin Oncol 1987;5:1968–76.PubMedGoogle Scholar
  73. 73.
    Nieweg MB, Greidanus J, De Vries EGE. A patient education program for a continuous infusion regimen on an outpatient basis. Cancer Nursing 1987;10:177–82.PubMedGoogle Scholar
  74. 74.
    Benvenuto JA, Adams SC, Vyas HM, Anderson RW. Pharmaceutical issues in infusion chemotherapy stability and compatibility. In: Lokich JJ, ed. Cancer chemotherapy by infusion. Chicago: Precept Press Inc., 1987:100–13.Google Scholar

Copyright information

© Bohn, Scheltema & Holkema 1988

Authors and Affiliations

  • Janke Greidanus
    • 1
  • Pax H. B. Willemse
    • 1
  • Donald R. A. Uges
    • 2
  • Evrard T. H. G. J. Oremus
    • 2
  • Zacharias J. de Langen
    • 3
  • Elisabeth G. E. de Vries
    • 1
  1. 1.Division of Medical Oncology, Department of Internal MedicineUniversity Hospital GroningenRB GroningenThe Netherlands
  2. 2.Department of Hospital PharmacyUniversity Hospital GroningenThe Netherlands
  3. 3.Department of Surgical OncologyUniversity Hospital GroningenThe Netherlands

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