Abstract
Background
The differences in toxicity of etoposide following continuous or bolus infusion are unknown.
Methods
We studied the schedule-dependent toxicity of high-dose etoposide when combined with high-dose cytarabine and idarubicin (IDEA) in 138 patients with acute leukemia. Four groups of patients were studied: group I, relapse; group II, secondary acute myeloid leukemia (AML); group III, de novo AML, age >60 years; and group IV, induction failure or blast crisis of myeloproliferative syndrome. Treatment for groups I–III was idarubicin 8 mg/m2 per day days 1–3, cytarabine 2000 mg/m2 once a day days 1–6, and etoposide 1600 mg/m2 total dose. Group IV treatment differed by cytarabine given twice daily days 1–6. Patients were randomized to etoposide as a continuous infusion days 1–6 or as a bolus infusion over 10 h on day 7.
Results
Continuous infusion etoposide produced significantly more oral mucositis than bolus etoposide. In groups I–III, comparing continuous and bolus etoposide, there was a median of 3 vs 0 days of grade 2 or more oral mucositis (P<0.0001) and 13.5 vs 0 days of total parenteral nutrition (TPN) (P=0.0003). Group IV patients had a median 7 vs 0 days of grade 2 or more oral mucositis (P<0.01) and 21 vs 7 days of TPN (P<0.003), respectively. There were no differences in hematologic recovery, length of hospital stay, complete remission rate or overall survival between the two etoposide schedules. Of groups I–III patients, 51% achieved complete remission, and 11% died from treatment-related complications.
Conclusion
The toxicity profile of high-dose etoposide is schedule-dependent with prolonged exposure producing significantly more non-hematologic toxicity.
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References
Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D, Cobcroft R, Whiteside MG, Kronenberg H, Ma D, Dodds A, Herrmann R, Szer J, Wolf MM, Young G, Group ALS (1990) Etoposide in acute nonlymphocytic leukemia. Blood 75:27
Hann I, Stevens R, Goldstone A, Rees J, Wheatley K, Gray R, Burnett A, the Adult and Childhood Leukaemia Working parties of the Medical Research Council (1997) Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council’s 10th AML Trial (MRC AML10). Blood 89:2311
Blume K, Forman S, O’Donnell M, Doroshow J, Krance R, Nademanee A, Snyder D, Schmidt G, Fahey J, Metter G, Hill L, Findley D, Sniecinski I (1987) Total body irradiation and high-dose etoposide: a new preparatory regimen for bone marrow transplantation in patients with advanced hematologic malignancies. Blood 69:1015
Blume KG, Kopecky KJ, Henslee-Downey JP, Forman SJ, Stiff PJ, LeMaistre CF, Appelbaum FR (1993) A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study. Blood 81:2187
Long G, Amylon M, Stockerl-Goldstein K, Negrin R, Chao N, Hu W, Nademanee A, Snyder D, Hoppe R, Vora N, Wong R, Niland J, Reichardt V, Forman S, Blume K (1997) Fractionated total-body irradiation, etoposide, and cyclophosphamide followed by allogeneic bone marrow transplantation for patients with high-risk or advanced-stage hematological malignancies. Biol Blood Marrow Transplant 3:324
Snyder D, Negrin R, O’Donnell M, Chao N, Amylon M, Long G, Nademanee A, Stein A, Parker P, Smith E, Somlo G, Margolin K, Molina A, Stepan D, Lipsett J (1994) Fractionated total-body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 94 patients with chronic myelogenous leukemia in chronic phase. Blood 84:1672
Chao N, Stein A, Long G, Negrin R, Amylon M, Wong R, Forman S, Blume K (1993) Busulfan/etoposide—initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81:319
Linker CA, Ries CA, Damon LE, Rugo HS, Wolf JL (1993) Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81:311
Linker CA, Ries CA, Damon LE, Rugo HS, Wolf JL (1998) Autologous bone marrow transplantation for acute myeloid leukemia using 4-hydroperoxycyclophosphamide-purged bone marrow and the busulfan/etoposide preparative regimen: a follow-up report. Bone Marrow Transplant 22:865
Linker C, Ries C, Damon L, Sayre P, Navarro W, Rugo H, Rubin A, Case D, Topolsky D, Brodsky I, Zamkoff K, Wolff J (2000) Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant 6:460
Dombernowsky P, Nissen N (1973) Schedule dependency of the antileukaemic activity of the podophyllotoxin-derivative VP16-213 (NSC 141540) in L1210 leukaemia. Acta Pathol Microbiol Immunol Scand 81:715
Cavalli F, Sontag R, Jungi J (1978) VP16-213 monotherapy for remission induction of small cell lung cancer. A randomized trial using three dosage schedules. Cancer Treat Rep 62:473
Van Echo D, Wiernik P, Aisner J (1980) High-dose VP16-213 (NSC 141540) for the treatment of patients with previously treated acute leukemia. Cancer Clin Trials 3:325
Slevin M, Clark P, Joel S, Malik S, Osborne R, Gregory W, Lowe D, Reznek R, Wrigley P (1989) A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 7:1333
Goldberg R, Jett J, Therneau T, Johnson P, Tschetter L, Krook J, Veeder M, Owen D, Etzell P, Andres D (1990) Bolus versus infusion regimens of etoposide and cisplatin in treatment of non-small cell lung cancer: A study of the North Central Cancer Treatment Group. J Natl Cancer Inst 82:1899
Clark P, Slevin M, Joel S (1994) A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity. J Clin Oncol 12:1427
Brown RA, Herzig RH, Wolff SN, Frei-Lahr D, Pineiro L, Bolwell BJ, Lowder JN, Harden EA, Hande KR, Herzig GP (1990) High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76:473
Wolff S, Fer M, McKay C, Hande K, Hainsworth J, Greco F (1983) High-dose VP16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study. J Clin Oncol 1:701
Spadea A, Petti M, Fazi P, Vegna M, Arcese W, Avvisati G, Spiriti M, Latagliata R, Meloni G, Testi A, Amadori S, Mandelli F (1993) Mitoxantrone, etoposide and intermediate-dose cytarabine (MEC): an effective regimen for poor risk acute myeloid leukemia. Leukemia 7:549
Carella A, Carlier P, Pungolino E, Resegotti L, Liso V, Stasi R, Montillo M, Iacopino P, Mirto S, Pagano L, Leoni F, Martelli F, Di Raimondo F, Porcellini A, de Riu L (1993) Idarubicin in combination with intermediate-dose cytarabine and VP-16 in the treatment of refractory or rapidly relapsed patients with acute myeloid leukemia. Leukemia 7:196
Archimbaud E, Thomas X, Leblond V, Michallet M, Fenaux P, Cordonnier C, Dreyfus F, Troussard X, Jaubert J, Travade P, Troncy J, Assouline D, Fiere D (1995) Timed sequential chemotherapy for previously treated patients with acute myeloid leukemia: long-term follow-up of the etoposide, mitoxantrone, and cytarabine-86 trial. J Clin Oncol 13:11
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 103:620
Leith C, Kopechy K, Godwin J, McConnell T, Slovak M, Chen I, Head D, Appelbaum F, Willman C (1997) Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 89:3323
Damon L, Mass R, Linker C (1989) The association between high-dose cytarabine neurotoxicity and renal insufficiency. J Clin Oncol 7:1563
Smith G, Damon L, Rugo H, Ries C, Linker C (1997) High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol 15:833
Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, Thomas ED (1988) Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 6:1562
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17:1244
Johnston L, Damon L, Ries C, Rugo H, Linker C (1994) High dose VP16 with intermediate dose cytarabine for high risk leukemia. Proc Am Soc Clin Oncol 13:303
Conover W, Iman R (1981) Rank transformations as a bridge between parametric and nonparametric statistics. Am Stat 35:124
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457
Gehan E (1965) A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52:15
Van Maanen J, Retel J, de Vries J, Pinedo H (1988) Mechanism of action of antitumor drug etoposide: a review. J Nat l Cancer Inst 80:1526
Dombret H, Chastang C, Fenaux P, Reiffers J, Bordessoule D, Bouabdallah R, Mandelli F, Ferrant A, Auzanneau G, Tilly H, Yver A, Degos L (1995) A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. New Engl J Med 332:1768
Stone R, Berg D, George S, Dogde R, Paciucci P, Schulman P, Lee E, Moore J, Powell B, Schiffer C (1995) Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. New Engl J Med 332:1671
Godwin J, Kopechy K, Head D, Willman C, Leith C, Hynes H, Balcerzak S, Appelbaum F (1998) A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031). Blood 91:3607
Witz F, Sadoun A, Perrin MC, Berthou C, Brière J, Cahn JY, Lioure B, Witz B, François S, Desablens B, Pignon B, Le Prisé PY, Audhuy B, Caillot D, Casassus P (1998) A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91:2722
Rowe JM, Andersen JW, Mazza JJ, Bennett JM, Paietta E, Hayes FA, Oette D, Cassileth PA, Stadtmauer EA, Wiernik PH (1995) 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: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86:457
Leoni F, Ciolli S, Giuliani G, Pascarella A, Caporale R, Salti F, Cervi L, Ferrini P (1995) Attenuated-dose idarubicin in acute myeloid leukaemia of the elderly: pharmacokinetic study and clinical results. Br J Haematol 90:169
Lazarus HM, Vogler WR, Burns CP, Winton EF (1989) High-dose cytosine arabinoside and daunorubicin as primary therapy in elderly patients with acute myelogenous leukemia. A phase I-II study of the Southeastern Cancer Study Group. Cancer 63:1055
Löwenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, Cauchie C, Peetermans M, Solbu G, Suciu S, et al (1989) On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group [see comments]. J Clin Oncol 7:1268
Petti M, Mandelli F, Avvisati G, Covelli A, Amadori S, Liso V, Leone G, De Laurenzi A, Leoni P, Neri A, Grignani F, Torlontano G, Deriu L, Caronia F (1989) High-dose cytarabine plus asparaginase in elderly patients with acute non-lymphocytic leukemia: a pilot multicentric study by the Italian cooperative group GIMEMA. Eur J Haematol 42:24
Preisler HD, Raza A, Barcos M, Azarnia N, Larson R, Walker I, Browman M, Grunwald H, D’Arrigo P, Doeblin T, Bloom M, Stein A, Logue G, Goldberg J, Kirshner J (1987) High-dose cytosine arabinoside as the initial treatment of poor-risk patients with acute nonlymphocytic leukemia: a Leukemia Intergroup study. J Clin Oncol 5:75
Feldman E, Seiter K, Damon L, Linker C, Rugo H, Ries C, Case D, Beer M, Ahmed T (1997) A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute myeloid leukemia. Leukemia 11:485
Bow E, Sutherland J, Kilpatrick M, Williams G, Clinch J, Shore T, Rubinger M, Schacter B (1996) Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide. J Clin Oncol 14:1345
Schiller G, Lee M (1997) Long-term outcome of high-dose cytarabine-based consolidation chemotherapy for older patients with acute myelogenous leukemia. Leuk Lymphoma 25:111
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This work was supported in part by research funds from Adria Laboratories and Kabi Pharmacia Inc.
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Damon, L.E., Johnston, L.J., Ries, C.A. et al. Treatment of acute leukemia with idarubicin, etoposide and cytarabine (IDEA). A randomized study of etoposide schedule. Cancer Chemother Pharmacol 53, 468–474 (2004). https://doi.org/10.1007/s00280-003-0758-x
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DOI: https://doi.org/10.1007/s00280-003-0758-x