Abstract
Etoposide has been used in the treatment of a wide variety of neoplasms, including small-cell lung cancer, Kaposi's sarcoma, testicular cancer, acute leukemia, and lymphoma. Its current therapeutic use is limited by myelosuppression, particularly neutropenia. Pharmacodynamic studies of etoposide show that this toxicity can be modeled using a modified Hill equation and that the dose intensity of etoposide can be successfully increased by adaptive control using this model. Significant influences on the degree of myelosuppression include the pretreatment leukocyte count, the performance status, the extent of prior erythrocyte transfusions, and the serum albumin level. In the past 7 years, interest has developed in a distinct subset of acute nonlymphocytic leukemia that is associated with prior exposure to etoposide. This syndrome has been described in several studies and is characterized by the lack of a preleukemic phase, M4 or M5 morphology, and distinct translocations involving the chromosome 11q23 region. In addition, secondary acute lymphocytic leukemias (involving 11q23) have also been associated with prior epipodophyllotoxin exposure.
Similar content being viewed by others
References
Aisner J, Lee EJ (1991) Etoposide: current and future status. Cancer 67: 215
Powis G (1985) Anticancer drug pharmacodynamics. Cancer Chemother Pharmacol 14: 177
Ratain MJ, Schilsky RL, Conley BA, et al (1990) Pharmacodynamics in cancer therapy. J Clin Oncol 8: 1739
Bennett CL, Sinkule JA, Schilsky RL, et al. (1987) Phase I clinical and pharmacological study of 72-hour continuous infusion etoposide in patients with advanced cancer. Cancer Res 47: 1952
Ratain MJ, Schilsky RL, Choi KE, et al (1989) Adaptive control of etoposide administration: impact of interpatient pharmacodynamic variability. Clin Pharmacol Ther 45: 226
Ratain MJ, Mick R, Schilsky RL, et al (1991) Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity. J Clin Oncol 9: 1480
Mick R, Ratain MJ (1991) Modeling interpatient pharmacodynamic variability of etoposide. J Natl Cancer Inst 83: 1560
Miller AA, Stewart CF, Tolley EA (1990) Clinical pharmacodynamics of continuous-infusion etoposide. Cancer Chemother Pharmacol 25: 361
Stewart CF, Pieper JA, Arbuck SG, et al (1989) Altered binding of etoposide in patients with cancer. Clin Pharmacol Ther 45: 49
Stewart CF, Fleming RA, Arbuck SG, et al (1990) Prospective evaluation of a model for predicting etoposide plasma protein binding in cancer patients. Cancer Res 50: 6854
Stewart CF, Arbuck SG, Fleming RA, et al (1991) Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther 50: 385
Minami H, Shimokata K, Saka H, et al (1993) Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer. J Clin Oncol 11: 1602
Gibaldi M, Perrier D (1982) Nonlinear pharmacokinetics. In: Pharmacokinetics. Marcel Dekker, New York, pp 221–269
Newbig RA (1990) The time course of drug action. In: Prat WB, Taylor P (eds) Principles of drug action, 3rd edn. Churchill Livingstone, New York, pp 297–365
Conley BA, Forrest A, Egorin MJ, et al (1989) Phase I trial using adaptive control dosing of hexamethylene bisacetamide (NSC 95580). Cancer Res 49: 3436
Evans WE, Rodman JH, Petros WP, et al (1990) Individualized doses of chemotherapy for children with acute lymphocytic leukemia (ALL) (abstract). Proc Am Soc Clin Oncol 9: 268
Egorin MJ, Van Echo DA, Tipping SJ, et al (1989) Pharmacokinetics and dosage reduction ofcis-diammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. Cancer Res 44: 5432
Strömgren AS, Sørensen BT, Jakobsen P, et al (1993) A limited sampling method for estimation of the etoposide area under the curve. Cancer Chemother Pharmacol 32: 226
Méresse V, Vassal G, Michon J, et al (1993) Combined continous infusion etoposide with high-dose cyclophosphamide for refractory neuroblastoma: a phase II study from the Société Française d'Oncologie Pédiatrique. J Clin Oncol 11: 630
Rivera GK, Pui CH, Crist WM (1993) The epipodophyllotoxins: both sides of the coin (letters). J Clin Oncol 11: 1624
Kamen BA, Buchanan GR, Winick NJ (1993) Reply to Ref. [20], J Clin Oncol 11: 1622 (Letter)
LeBeau MM, Albain KS, Larson RA, et al (1986) Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia and further evidence for characteristic abnormalities of chromosomes No. 5 and 7. J Clin Oncol 4: 325
Ratain MJ, Kaminer LS, Bitran JD, et al (1987) Acute nonlymphocytic leukemia following etoposide and cisplatin combination chemotherapy for advanced non-small cell carcinoma of the lung. Blood 70: 1412–1417
Weh HJ, Kabisch H, Ladbeck G, et al (1986) Translocation (9;11)(p21;q23) in child with acute monoblastic leukemia following 2-1/2 years after successful chemotherapy for neuroblastoma. J Clin Oncol 4: 1518–1520
DeWald GW, Morrison-DeLap AJ, Schuchard KA, et al (1983) A possible specific chromosome marker for monocytic leukemia: three more patients with t(9;11)(p22;q24) and another with t(11;17)(q24;q21), each with acute monoblastic leukemia. Cancer Genet Cytogenet 8: 203–212
Fenaux P, Jouet JP, Bauters F, et al (1987) Translocation t(9;11)(p21;q23) with acute myelomonocytic leukemia after chemotherapy for osteosarcoma: good response to antileukemic drugs. J Clin Oncol 5: 1304–1305
Pui CH, Behm FG, Raimondi SC, et al (1989) Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 321: 136–142
Pui CH, Hancock ML, Raimondi SC, et al (1990) Myeloid neoplasia in children treated for solid tumors. Lancet 336: 417–421
Pui CH, Ribeiro RC, Hancock ML, et al (1991) Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325: 1682–1687
Pedersen-Bjergaard J, Daugaard J, Dauggard G, Hansen SW, et al (1991) Increased risk of myelodysplasia and leukemia after etoposide, cisplatin, and bleomycin for germ-cell tumors. Lancet 338: 359–363
Winick NJ, McKenna RW, Shuster JJ, et al (1993) Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. J Clin Oncol 11: 209–217
Whitlock JA, Greer JP, Lukens JN (1991) Epipodophyllotoxinrelated leukemia. Cancer 68: 600–604
Nichols CR, Breeden SE, Loehrer PJ, et al (1993) Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols. J Natl Cancer Inst 85: 36–40
Bajorin DF, Motzer RJ, Rodriguez E, et al (1993) Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst 85: 60–62
Sugita K, Furukawa T, Tsuchida M, et al (1993) High frequency of etoposide (VP-16)-related secondary leukemia in children with non-Hodgkin's lymphoma. Am J Pediatr Hematol Oncol 15: 99–104
Zeimet AG, Thaler J, Abfalter E, et al (1992) Secondary leukaemias after etoposide (letter). Lancet 340: 379–380
Haupt R, Comelli A, Rosanda C, et al (1993) Acute myeloid leukemia after single-agent treatment with etoposide for Langerhans' cell histiocytosis of bone. Am J Pediatr Hematol Oncol 15: 255–257
Bokemeyer C, Freund M, Schmoll HJ, et al (1992) Secondary lymphoblastic leukemia following treatment of a malignant germ cell tumor. Ann Oncol 3: 771–774
Auxenfants E, Morel P, Lai JL, et al (1992) Secondary acute lymphoblastic leukemia with t(4;11): report on two cases and review of the literature. Ann Hematol 65: 143–146
Pui Ch, Raimondia SC, Crist WM (1992) Secondary leukaemias after epipodophyllotoxins (letter). Lancet 340: 672–673
Bokemeyer C, Schmoll HJ (1993) Secondary neoplasms following treatment of malignant germ cell tumors. J Clin Oncol 11: 1703–1709
Smith MA, Rubinstein L, Cazenave L, et al (1993) Report of the Cancer Therapy Evaluation Program monitoring plan for secondary acute myeloid leukemia follwing treatment with epipodophyllotoxins. J Natl Cancer Inst 85: 554–558
Maraschin J, Dutrillaux B, Aurias A (1990) Chromosome aberrations induced by etoposide (VP-16) are not random. Int J Cancer 46: 808–812
Felix CA, Winick NJ, Negrini M, et al (1993) Common region ofALL-1 gene disrupted in epipodophyllotoxin-related secondary acute myeloid leukemia. Cancer Res 53: 2954–2956
DeVore R, Whitlock J, Hainsworth JH, et al (1989) Therapy-related acute nonlymphocytic leukemia with monocytic features and rearrangement of chromosome 11q. Ann Intern Med 110: 740–742
Pedersen-Bjergaard J, Philip P (1991) Balanced translocations involving chromosome bands 11q23 and 21q22 are highly characteristic of myelodysplasia and leukemia following therapy with cytostatic agents targeting at DNA-topoisomerase II (letter). J Clin Oncol 9: 1147–1148
Cleaver JE (1991) Correlations between sister chromatid exchange frequencies and replicon size: a model for the mechanism of SCE production. Exp Cell Res 136: 27–30
Tominaga K, Shinkai T, Saijo N, et al (1986) Cytogenetic effects of etoposide (VP-16) on human lymphocytes, with special reference to the relation between sister chromatid exchange and chromatid breakage. Jpn J Cancer Res 77: 385–391
Tominaga K, Shinkai T, Saijo N, et al (1986) Cytogenetic effects of multiagent chemotherapy on the peripheral lymphocytes of patients with small cell lung cancer. Jpn J Cancer Res 77: 1241–1248
Shinkai T, Saijo N, Eguchi K, et al (1989) Serial measurements of sister chromatid exchanges in the peripheral lymphocytes of patients with lung cancer receiving chemotherapy in relation to bone marrow toxicity. Jpn J Cancer Res 80: 783–786
Osanto S, Thijssen JCP, Woldering VM, et al (1991) Increased frequency of chromosomal damage in peripheral blood lymphocytes up to nine years following curative chemotherapy of patients with testicular carcinoma. Environ Mol Mutagen 17: 71–78
Pedersen-Bjergaard J, Sigsgaard TC, Nielsen D, et al (1992) Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4-epidoxorubicin and cisplatin or cyclophosphamide for breast cancer. J Clin Oncol 10: 1444–1451
Sandoval C, Pui CH, Bowman LC, et al (1993) Secondary acute myeloid leukemia in children previously treated with alkylating agents, intercalating topoisomerase II inhibitors, and irradiation. J Clin Oncol 11: 1039–1045
Amylong MD, Carroll AJ, Link MP, et al (1992) Second malignancies in children treated with teniposide (VM-26) for T-cell lymphoid malignancy: a role for asparaginase? [A Pediatric Oncology Group (POG) study]. Blood 80 [Suppl 1]: 206a
Winick N, Buchanan GR, Kamen BA (1993) Secondary acute myeloid leukemia in Hispanic children (letter). J Clin Oncol 11: 1433
Sackett DL, Haynes RB, Tugwell P (1985) Clinical epidemiology: a basic science for clinical medicine. Little, Brown, Boston
Author information
Authors and Affiliations
Additional information
This work was supported in part by NIH training grant 5T32-GM07019 (to K.K.)
Rights and permissions
About this article
Cite this article
Kobayashi, K., Ratain, M.J. Pharmacodynamics and long-term toxicity of etoposide. Cancer Chemother. Pharmacol. 34 (Suppl 1), S64–S68 (1994). https://doi.org/10.1007/BF00684866
Issue Date:
DOI: https://doi.org/10.1007/BF00684866