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. 2001 Feb;84(3):313–320. doi: 10.1054/bjoc.2000.1611

A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplanation

J T Hartmann 1, A von Vangerow 1, L M Fels 2,3, S Knop 1, H Stolte 2,3, L Kanz 1, C Bokemeyer 1
PMCID: PMC2363753  PMID: 11161394

Abstract

This pilot study evaluates the degree of side effects during high-dose chemotherapy (HD-VIC) plus autologous bone marrow transplant (HDCT) and its possible prevention by the cytoprotective thiol-derivate amifostine. Additionally, the in-patient medical costs of both treatment arms were compared. 40 patients with solid tumours were randomized to receive HD-VIC chemotherapy with or without amifostine (910 mg/m2 at day 1–3) given as a short infusion prior to carboplatin and ifosfamide. Patients were stratified according to pretreatment. HDCT consisted of an 18 h infusion of carboplatin (500 mg/m2/d over 18 h), ifosfamide (4 g/m2/d over 4 h) and etoposide (500 mg/m2/d) all given for 3 consecutive days. All patients received prophylactic application of G-CSF (5 μg kg−1 subcutaneously) to ameliorate neutropenia after treatment. Patients were monitored for nephrotoxicity, gastrointestinal side effects, haematopoietic recovery, as well as frequency of fever and infections. The median fall of the glomerular filtration rate (GFR) was 10% from baseline in the amifostine group (105 to 95 ml min−1) and 37% in the control patient group (107 to 67 ml min−1) (P< 0.01). Amifostine-treated patients revealed a less pronounced increase in albumine and low molecular weight protein urinary excretion. Stomatitis grade III/IV occurred in 25% without versus 0% of patients with amifostine (P = 0.01). Acute nausea/vomiting was frequently observed immediately during or after the application of amifostine despite intensive antiemetic prophylaxis consisting of 5-HT3-receptor antagonists/dexamethasone/trifluorpromazine. However, delayed emesis occurred more often in the control patients. Engraftment of neutrophil (> 500 μl−1) and thrombocytes (> 25 000 μl−1)were observed at days 9 versus 10 and 10 versus 12, respectively, both slightly in favour of the amifostine arm. In addition, a lower number of days with fever and a shortened duration of hospital stay were observed in the amifostine arm. The reduction of acute toxicity observed in the amifostine arm resulted in 30% savings in costs for supportive care (Euro 4396 versus Euro 3153 per patient). Taking into account the drug costs of amifostine, calculation of in-patient treatment costs from the start of chemotherapy to discharge revealed additional costs of Euro 540 per patient in the amifostine arm. This randomized pilot study indicates that both organ and haematotoxicity of HD-VIC chemotherapy can be ameliorated by the use of amifostine. Additionally, a nearly complete preservation of GFR was observed in amifostine-treated patients which may be advantageous if repetitive cycles of HDCT are planned. Larger randomized trials evaluating amifostine cytoprotection during high-dose chemotherapy are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: toxicity, high-dose chemotherapy, PBSC transplantation, cytoprotection, amifostine, pharmacoeconomics

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Footnotes

Presented in part at the 35th Proceedings of the American Society of Clinical Oncology, Atlanta, Georgia, USA, May 1518, 1999. This work represents part of the thesis of A. von Vangerow at the Dept. Hematology/Oncology, University of Tübingen.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Attal M., Harousseau J. L., Stoppa A. M., Sotto J. J., Fuzibet J. G., Rossi J. F., Casassus P., Maisonneuve H., Facon T., Ifrah N. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91–97. doi: 10.1056/NEJM199607113350204. [DOI] [PubMed] [Google Scholar]
  2. Barnett M. J., Coppin C. M., Murray N., Nevill T. J., Reece D. E., Klingemann H. G., Shepherd J. D., Nantel S. H., Sutherland H. J., Phillips G. L. High-dose chemotherapy and autologous bone marrow transplantation for patients with poor prognosis nonseminomatous germ cell tumours. Br J Cancer. 1993 Sep;68(3):594–598. doi: 10.1038/bjc.1993.392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bennett C. L., Armitage J. L., Buchner D., Gulati S. Economic analysis in phase III clinical cancer trials. Cancer Invest. 1994;12(3):336–342. doi: 10.3109/07357909409023033. [DOI] [PubMed] [Google Scholar]
  4. Bennett C. L., Stinson T. J., Tallman M. S., Stadtmauer E. A., Marsh R. W., Friedenberg W., Lazarus H. M., Kaminer L., Golub R. M., Rowe J. M. Economic analysis of a randomized placebo-controlled phase III study of granulocyte macrophage colony stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia. Eastern Cooperative Oncology Group (E1490). Ann Oncol. 1999 Feb;10(2):177–182. doi: 10.1023/a:1008318930947. [DOI] [PubMed] [Google Scholar]
  5. Beyer J., Rick O., Weinknecht S., Kingreen D., Lenz K., Siegert W. Nephrotoxicity after high-dose carboplatin, etoposide and ifosfamide in germ-cell tumors: incidence and implications for hematologic recovery and clinical outcome. Bone Marrow Transplant. 1997 Nov;20(10):813–819. doi: 10.1038/sj.bmt.1700980. [DOI] [PubMed] [Google Scholar]
  6. Broun E. R., Nichols C. R., Tricot G., Loehrer P. J., Williams S. D., Einhorn L. H. High dose carboplatin/VP-16 plus ifosfamide with autologous bone marrow support in the treatment of refractory germ cell tumors. Bone Marrow Transplant. 1991 Jan;7(1):53–56. [PubMed] [Google Scholar]
  7. Budd G. T., Ganapathi R., Wood L., Snyder J., McLain D., Bukowski R. M. Approaches to managing carboplatin-induced thrombocytopenia: focus on the role of amifostine. Semin Oncol. 1999 Apr;26(2 Suppl 7):41–50. [PubMed] [Google Scholar]
  8. Calvert A. H., Newell D. R., Gumbrell L. A., O'Reilly S., Burnell M., Boxall F. E., Siddik Z. H., Judson I. R., Gore M. E., Wiltshaw E. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989 Nov;7(11):1748–1756. doi: 10.1200/JCO.1989.7.11.1748. [DOI] [PubMed] [Google Scholar]
  9. Detsky A. S., Naglie I. G. A clinician's guide to cost-effectiveness analysis. Ann Intern Med. 1990 Jul 15;113(2):147–154. doi: 10.7326/0003-4819-113-2-147. [DOI] [PubMed] [Google Scholar]
  10. Eisenberg J. M. Clinical economics. A guide to the economic analysis of clinical practices. JAMA. 1989 Nov 24;262(20):2879–2886. doi: 10.1001/jama.262.20.2879. [DOI] [PubMed] [Google Scholar]
  11. Elias A. D., Ayash L. J., Wheeler C., Schwartz G., Tepler I., Gonin R., McCauley M., Mazanet R., Schnipper L., Frei E., 3rd Phase I study of high-dose ifosfamide, carboplatin and etoposide with autologous hematopoietic stem cell support. Bone Marrow Transplant. 1995 Mar;15(3):373–379. [PubMed] [Google Scholar]
  12. Fayers P. M., Hand D. J. Generalisation from phase III clinical trials: survival, quality of life, and health economics. Lancet. 1997 Oct 4;350(9083):1025–1027. doi: 10.1016/s0140-6736(97)03053-5. [DOI] [PubMed] [Google Scholar]
  13. Fetscher S., Brugger W., Engelhardt R., Kanz L., Hasse J., Frommhold H., Lange W., Mertelsmann R. Standard- and high-dose etoposide, ifosfamide, carboplatin, and epirubicin in 100 patients with small-cell lung cancer: a mature follow-up report. Ann Oncol. 1999 May;10(5):561–567. doi: 10.1023/a:1026453922931. [DOI] [PubMed] [Google Scholar]
  14. Fields K. K., Elfenbein G. J., Lazarus H. M., Cooper B. W., Perkins J. B., Creger R. J., Ballester O. F., Hiemenz J. H., Janssen W. E., Zorsky P. E. Maximum-tolerated doses of ifosfamide, carboplatin, and etoposide given over 6 days followed by autologous stem-cell rescue: toxicity profile. J Clin Oncol. 1995 Feb;13(2):323–332. doi: 10.1200/JCO.1995.13.2.323. [DOI] [PubMed] [Google Scholar]
  15. Gelmon K., Eisenhauer E., Bryce C., Tolcher A., Mayer L., Tomlinson E., Zee B., Blackstein M., Tomiak E., Yau J. Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol. 1999 Oct;17(10):3038–3047. doi: 10.1200/JCO.1999.17.10.3038. [DOI] [PubMed] [Google Scholar]
  16. Gianni A. M., Bregni M., Siena S., Brambilla C., Di Nicola M., Lombardi F., Gandola L., Tarella C., Pileri A., Ravagnani F. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med. 1997 May 1;336(18):1290–1297. doi: 10.1056/NEJM199705013361804. [DOI] [PubMed] [Google Scholar]
  17. Glover D., Glick J. H., Weiler C., Hurowitz S., Kligerman M. M. WR-2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol. 1986 Apr;4(4):584–588. doi: 10.1200/JCO.1986.4.4.584. [DOI] [PubMed] [Google Scholar]
  18. Goren M. P., Wright R. K., Horowitz M. E., Pratt C. B. Ifosfamide-induced subclinical tubular nephrotoxicity despite mesna. Cancer Treat Rep. 1987 Feb;71(2):127–130. [PubMed] [Google Scholar]
  19. Haioun C., Lepage E., Gisselbrecht C., Bastion Y., Coiffier B., Brice P., Bosly A., Dupriez B., Nouvel C., Tilly H. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 1997 Mar;15(3):1131–1137. doi: 10.1200/JCO.1997.15.3.1131. [DOI] [PubMed] [Google Scholar]
  20. Hartmann J. T., Fels L. M., Franzke A., Knop S., Renn M., Maess B., Panagiotou P., Lampe H., Kanz L., Stolte H. Comparative study of the acute nephrotoxicity from standard dose cisplatin +/- ifosfamide and high-dose chemotherapy with carboplatin and ifosfamide. Anticancer Res. 2000 Sep-Oct;20(5C):3767–3773. [PubMed] [Google Scholar]
  21. Hartmann J. T., Fels L. M., Knop S., Stolt H., Kanz L., Bokemeyer C. A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs. 2000 Aug;18(3):281–289. doi: 10.1023/a:1006490226104. [DOI] [PubMed] [Google Scholar]
  22. Hartmann J. T., Kanz L., Bokemeyer C. Diagnosis and treatment of patients with testicular germ cell cancer. Drugs. 1999 Aug;58(2):257–281. doi: 10.2165/00003495-199958020-00004. [DOI] [PubMed] [Google Scholar]
  23. Hartmann J. T., Kollmannsberger C., Kanz L., Bokemeyer C. Platinum organ toxicity and possible prevention in patients with testicular cancer. Int J Cancer. 1999 Dec 10;83(6):866–869. doi: 10.1002/(sici)1097-0215(19991210)83:6<866::aid-ijc34>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  24. Kemp G., Rose P., Lurain J., Berman M., Manetta A., Roullet B., Homesley H., Belpomme D., Glick J. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol. 1996 Jul;14(7):2101–2112. doi: 10.1200/JCO.1996.14.7.2101. [DOI] [PubMed] [Google Scholar]
  25. Linch D. C., Winfield D., Goldstone A. H., Moir D., Hancock B., McMillan A., Chopra R., Milligan D., Hudson G. V. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993 Apr 24;341(8852):1051–1054. doi: 10.1016/0140-6736(93)92411-l. [DOI] [PubMed] [Google Scholar]
  26. Margolin K., Doroshow J. H., Ahn C., Hamasaki V., Leong L., Morgan R., Raschko J., Shibata S., Somlo G., Tetef M. Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support. J Clin Oncol. 1996 Oct;14(10):2631–2637. doi: 10.1200/JCO.1996.14.10.2631. [DOI] [PubMed] [Google Scholar]
  27. Philip T., Guglielmi C., Hagenbeek A., Somers R., Van der Lelie H., Bron D., Sonneveld P., Gisselbrecht C., Cahn J. Y., Harousseau J. L. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7;333(23):1540–1545. doi: 10.1056/NEJM199512073332305. [DOI] [PubMed] [Google Scholar]
  28. Rizzieri D. A., Vredenburgh J. J., Jones R., Ross M., Shpall E. J., Hussein A., Broadwater G., Berry D., Petros W. P., Gilbert C. Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support. J Clin Oncol. 1999 Oct;17(10):3064–3074. doi: 10.1200/JCO.1999.17.10.3064. [DOI] [PubMed] [Google Scholar]
  29. Rosti G., Albertazzi L., Salvioni R., Pizzocaro G., Cetto G. L., Bassetto M. A., Marangolo M. High-dose chemotherapy supported with autologous bone marrow transplantation (ABMT) in germ cell tumors: a phase two study. Ann Oncol. 1992 Dec;3(10):809–812. doi: 10.1093/oxfordjournals.annonc.a058100. [DOI] [PubMed] [Google Scholar]
  30. Russell L. B., Gold M. R., Siegel J. E., Daniels N., Weinstein M. C. The role of cost-effectiveness analysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine. JAMA. 1996 Oct 9;276(14):1172–1177. [PubMed] [Google Scholar]
  31. Savarese D. M., Hsieh C., Stewart F. M. Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors. J Clin Oncol. 1997 Aug;15(8):2981–2995. doi: 10.1200/JCO.1997.15.8.2981. [DOI] [PubMed] [Google Scholar]
  32. Siegert W., Beyer J., Strohscheer I., Baurmann H., Oettle H., Zingsem J., Zimmermann R., Bokemeyer C., Schmoll H. J., Huhn D. High-dose treatment with carboplatin, etoposide, and ifosfamide followed by autologous stem-cell transplantation in relapsed or refractory germ cell cancer: a phase I/II study. The German Testicular Cancer Cooperative Study Group. J Clin Oncol. 1994 Jun;12(6):1223–1231. doi: 10.1200/JCO.1994.12.6.1223. [DOI] [PubMed] [Google Scholar]
  33. Treskes M., van der Vijgh W. J. WR2721 as a modulator of cisplatin- and carboplatin-induced side effects in comparison with other chemoprotective agents: a molecular approach. Cancer Chemother Pharmacol. 1993;33(2):93–106. doi: 10.1007/BF00685326. [DOI] [PubMed] [Google Scholar]
  34. Wadler S., Haynes H., Beitler J. J., Goldberg G., Holland J. F., Hochster H., Bruckner H., Mandeli J., Smith H., Runowicz C. Management of hypocalcemic effects of WR2721 administered on a daily times five schedule with cisplatin and radiation therapy. The New York Gynecologic Oncology Group. J Clin Oncol. 1993 Aug;11(8):1517–1522. doi: 10.1200/JCO.1993.11.8.1517. [DOI] [PubMed] [Google Scholar]
  35. Wagstaff A. J., Ward A., Benfield P., Heel R. C. Carboplatin. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs. 1989 Feb;37(2):162–190. doi: 10.2165/00003495-198937020-00005. [DOI] [PubMed] [Google Scholar]
  36. Wilson W. H., Jain V., Bryant G., Cowan K. H., Carter C., Cottler-Fox M., Goldspiel B., Steinberg S. M., Longo D. L., Wittes R. E. Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors. J Clin Oncol. 1992 Nov;10(11):1712–1722. doi: 10.1200/JCO.1992.10.11.1712. [DOI] [PubMed] [Google Scholar]
  37. Wright J. E., Elias A., Tretyakov O., Holden S., Andersen J., Wheeler C., Schwartz G., Antman K., Rosowsky A., Frel E., 3rd High-dose ifosfamide, carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity. Cancer Chemother Pharmacol. 1995;36(4):345–351. doi: 10.1007/BF00689053. [DOI] [PubMed] [Google Scholar]
  38. Zittoun R. A., Mandelli F., Willemze R., de Witte T., Labar B., Resegotti L., Leoni F., Damasio E., Visani G., Papa G. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med. 1995 Jan 26;332(4):217–223. doi: 10.1056/NEJM199501263320403. [DOI] [PubMed] [Google Scholar]
  39. van Dam F. S., Schagen S. B., Muller M. J., Boogerd W., vd Wall E., Droogleever Fortuyn M. E., Rodenhuis S. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst. 1998 Feb 4;90(3):210–218. doi: 10.1093/jnci/90.3.210. [DOI] [PubMed] [Google Scholar]

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