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/m2at 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−1subcutaneously) 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
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References
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C and Bataille R (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 335: 91–97
Barnett MJ, Coppin CM, Murray N, Nevill TJ, Reece-DE Klingemann-HG, Shepherd-JD Nantel-SH and Sutherland-HJ Phillips-GL (1993) High dose chemotherapy and autologus bone marrow transplantation for patients with poor prognosis nonseminomatous germ cell tumours. Br J Cancer 68: 594–598
Bennett CL, Armitage JL, Buchner D and Gulati S (1994) Economic analysis in phase III clinical cancer trials. Cancer Invest 12: 336–342
Bennett CL, Stinson TJ, Tallman MS, Stadtmauer EA, Marsh-RW Friedenberg W, Lazarus HM, Kaminer L, Golub RM and Rowe JM (1999) 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. Ann Oncol 10: 177–182
Beyer J, Rick O, Weinknecht S, Kingreen D and Lenz K (1997) Nephrotoxicity after high dose carboplatin, etoposide and ifosfamide in germ-cell tumors: incidence and implications for hematologic recovery and clinical outcome. Bone Marrow Transplant 20: 813–819
Broun ER, Nichols CR, Tricot G, Loehrer PJ, Williams SD and Einhorn LH (1991) High dose carboplatin/VP-16 plus ifosfamide with autologous bone marrow support in the treatment of refractory germ cell tumors. Bone Marrow Transplant 7: 53–56
Budd GT, Ganapathi R, Wood L, Snyder J, McLain D and Bukowski RM (1999) Approaches to managing carboplatin induced thrombocytopenia: Focus on the role of amifostine. Sem Oncol 26: 41–50, (suppl 7)
Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME and Wiltshaw E (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748–1756
Detsky AS and Naglie IG (1990) A clinician’s guide to cost effectiveness analysis. Ann Intern Med 113: 147–154
Eisenberg JM (1989) Clinical economics: A guide to the economic analysis of clinical practices. JAMA 262: 2879–2886
Elias AD, Ayash LJ, Wheeler C, Schwartz G, Tepler I, Gonin R, McCauley M, Mazanet R, Schnipper L and Frei E (1995) Phase I study of high dose ifosfamide, carboplatin, etoposide with autologous hematopoietic stem cell support. Bone Marrow Transplant 15: 373–379
Elias A, Richardsen P, Tretyakov O, Avigan A, Warren D, Arthur T, McCauley M, Wright J and Frei E (2000) Amifostine with high dose ifosfamide, carboplatin, and etoposide with hematopoietic stem cell support. Proc Am Soc Clin Oncol 19: 51a (abstr. 197)
Fayers PM and Hand DJ (1999) Generalisation from phase III clinical trials: survival, quality of life, and health economics. Lancet 350: 1025–1027
Fetscher S, Brugger W, Engelhardt R, Kanz L, Hasse J, Frommhold H, Lange W and Mertelsmann R (1999) Standard and high dose etoposide, ifosfamide, carboplatin, and epirubicin in 100 patients with small cell lung cancer: A mature follow up report. Ann Oncol 10: 561–567
Fields KK, Elfenbein GJ, Lazarus HM, Cooper BW, Perkins JB, Creger RJ, Ballester OF, Hiemenz JH, Janssen WE and Zorsky PE (1995) Maximum tolerated doses of ifosfamide, carboplatin, and etoposide given over 6 days followed by autologous stem cell rescue: toxicity profile. J Clin Oncol 13: 323–332
Gelmon K, Eisenhauer E, Bryce C, Tolcher A, Mayer L, Tomlinson E, Zee B, Blackstein M, Tomiak E, Yau J, Batist G, Fisher B and Iglesias J (1999) Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol 17: 3038–3047
Gianni AM, Bregni M, Siena S, Brambilla C, DiNicola M, Lombardi F, Gandola L, Tarella C, Pileri A, Ravagnani F, Valagussa P, Bonadonna G, Stern AC, Magni M and Caracciolo D (1997a) High dose chemotherapy and autologous bone marrow transplantation compared with MACOP B in aggressive B cell lymphoma. N Engl J Med 336: 1290–1297
Gianni AM, Siena S, Bregni M, DiNicola M, Orefice S, Cusumano F, Salvadori B, Luini A, Greco M, Zucali R, Rilke F, Zambetti M, Valagussa P and Bonadonna G (1997b) Efficacy, toxicity, and applicability of high dose sequential chemotherapy as adjuvant treatment in operable breaset cancer with 10 or more involved axillary nodes: five year results. J Clin Oncol 15: 2312–2321
Glasziou PP and Mitchell AS (1996) Use of pharmacoeconomic data by regulatory authorities. Quality of life and pharmacoeconomics in clinical trials, Spiker B (ed) pp. 1141–1147. Lippinciott-Raven: Philadelphia, PA
Glover D, Glick JH, Weiler C, Hurowitz S and Kligerman MM (1986) WR 2721 protects against the hematologic toxicity of cyclophosphamide: a controlled phase II trial. J Clin Oncol 4: 584–588
Goren MP, Wright RK, Horowitz ME and Pratt CB (1987) Ifosfamide-induced subclinical tubular nephrotoxicity despite mesna. Cancer Treat Rep 71: 127–130
Haioun C, Lepage E, Gisselbrecht C, Bastion Y, Coiffier B, Brice P, Bosly A, Dupriez B, Nouvel C, Tilly H, Lederlin P, Biron P, Briere J, Gaulard P and Reyes F (1997) 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. J Clin Oncol 15: 1131–1137
Hartmann JT, Kanz L and Bokemeyer C (1999a) Diagnosis and treatment of patients with testicular germ cell cancer. Drugs 58: 257–281
Hartmann JT, Kollmannsberger C, Kanz L and Bokemeyer C (1999b) Platinum organ toxicity and its possible prevention in patients with testicular cancer. Int J Cancer 83: 866–869
Hartmann JT, Knop S, Fels LM, van Vangerow A, Stolte H, Kanz L and Bokemeyer C (2000a) The use of reduced doses of amifostine to ameloriate nephrotoxicity of cisplatin/ifosfamide-based chemotherapy in patients with solid tumors. Anti-Cancer Drugs 11: 1–6
Hartmann JT, Fels LM, Knop S, Stolte H, Kanz L and Bokemeyer C (2000b) A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination chemotherapy with or without amifostine in patients with solid tumors. Invest New Drugs 18: 281–289
Hartmann JT, Fels LM, Franzke A, Knop S, Renn M, Maeß B, Panagiotou P, Lampe H, Kanz L, Stolte H and Bokemeyer C (2000c) Evaluation of the acute nephrotoxicity of cisplatin- and high dose carboplatin based combination chemotherapy. Anticancer Research 20: 3767–3774
Kemp G, Rose P, Lurain J, Berman M, Manetta A, Roullet B, Homesley H, Belpomme D and Glick J (1996) 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 14: 2101–2112
Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D and Hudson GV (1993) Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet 341: 1051–1054
Margolin K, Doroshow JH, Ahn C, Hamasaki V, Leong L, Morgan R, Raschko J, Shibata S, Somlo G and Tetef M (1996) Treatment of germ cell cancer with two cycles of high dose ifosfamide, carboplatin, and etoposide with autologous stem cell support. J Clin Oncol 14: 2631–2637
Philip T, Guglielmi C, Hagenbeek A, Somers R, van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, Coiffier B, Biron P, Mandelli F and Chauvin F (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy sensitive non Hodgkin’s lymphoma. N Engl J Med 333: 1540–1545
Rizzieri DA, Vredenburgh JJ, Jones R, Ross M, Shpall EJ, Hussein A, Broadwater G, Berry D, Petros WP, Gilbert C, Affronti ML, Coniglio D, Rubin P, Elkordy M, Long GD, Chao NJ and Peters WP (1999) 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 17: 3064–3074
Rosti G, Albertazzi L, Salvioni R, Pizzocaro G, Cetto GL, Bassetto MA and Marangolo M (1992) High dose chemotherapy supported with autologous bone marrow transplantation (ABMT) in germ cell tumors: a phase two study. Ann Oncol 3: 809–812
Russell LB, Gold MR, Siegel JE, Daniels N and Weinstein MC (1996) The role of cost effectiveness analysis in health and medicine. JAMA 276: 1172–1177
Savarese DEM, Hsieh C and Stewart FM (1997) Clinical impact of chemotherapy dose escalation in patients with hematologic malignancies and solid tumors. J Clin Oncol 15: 2981–2995
Siegert W, Beyer J, Strohscheer I, Baurmann H, Oettle H, Zingsem J, Zimmermann R, Bokemeyer C, Schmoll HJ and Huhn D (1994) 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 Arm. J Clin Oncol 12: 1223–1231
Treskes M and van der Vijgh W (1993) WR2721 as a modulator of cisplatin- and carboplatin-induced side effects in comparison with other chemoprotective agents: a molecular approach. Cancer Chemother Pharmacol 33: 93–106
van Dam FSAM, Schagen SB, Muller MJ, Boogerd W, von der Wall E, Fortuyn MED and Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high risk breast cancer: High dose versus standard dose chemotherapy. J Natl Cancer Inst 90: 210–218
Wadler S, Haynes H, Beitler JJ, Goldberg G, Holland JF, Hochster H, Bruckner H, Mandeli J, Smith H and Runowicz C (1993) 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 11: 1517–1522
Wagstaff AJ, Ward A, Benfield P and Heel RC (1989) Carboplatin. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of cancer. Drugs 37: 162–190
Wilson WH, Jain V, Bryant G, Cowan KH, Carter C, Cottler Fox M, Goldspiel B Steinberg SM, Longo DL and Wittes RE (1992) 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 10: 1712–1722
Wright JE, Elias A, Tretyakov O, Holden S, Andersen J, Wheeler C, Schwartz G, Antman K, Rosowsky A and Frei E (1995) High dose ifosfamide, carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity. Cancer Chemother Pharmacol 36: 345–351
Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L, Leoni F, Damasio E, Visani G and Papa G (1995) Autologous or allogeneic bone marrow tranplantation compared with intensive chemotheraphy in acute myelogenous leukemia. Europeon Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia co-opearative Arms. N Engl. J Med 332: 217–223
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Presented in part at the 35th Proceedings of the American Society of Clinical Oncology, Atlanta, Georgia, USA, May 15–18, 1999. This work represents part of the thesis of A. von Vangerow at the Dept. Hematology/Oncology, University of Tübingen.
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Hartmann, J., von Vangerow, A., Fels, L. et al. A randomized trial of amifostine in patients with high-dose VIC chemotherapy plus autologous blood stem cell transplanation. Br J Cancer 84, 313–320 (2001). https://doi.org/10.1054/bjoc.2000.1611
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DOI: https://doi.org/10.1054/bjoc.2000.1611
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