A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity.

Clark, Peter; Slevin, M. L.; Joel, S. P.; Osborne, Richard; Talbot, D; Johnson, Paul W.; Reznek, RH; Masud, Tahsin; Gregory, WM; Wrigley, P. F. M.

doi:10.1200/jco.1994.12.7.1427

Cited by 104 publications

(45 citation statements)

References 20 publications

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“…This clearance is higher than that reported in seven previous studies in children 1,6,9,12,28 and 14 previous studies in adults. 1,2,7,11,13 One possible explanation for the very high clearance we observed is that the previous 4 week course of prednisone may have induced CYP3A4 43 metabolism of etoposide, 40 a finding consistent with our previous observations of enhanced P450 metabolism following remission induction. 44 In summary, although our data should be interpreted with caution due to their retrospective nature and the small number of patients, they represent the only pharmacokinetic data available in identically treated patients who did and did not go on to develop epipodophyllotoxin-associated AML, and may provide insights into variables that deserve further study.…”

Section: Figuresupporting

confidence: 81%

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Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia

Relling

Yanishevski

Němec³

et al. 1998

Leukemia

176

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Etoposide, an effective agent for acute lymphoblastic leukemia (ALL), can cause secondary acute myeloid leukemia (AML) in a subset of patients. Our objectives were to determine whether patients who develop secondary AML displayed altered etoposide pharmacokinetics or other pharmacologic characteristics compared to identically treated patients who did not develop AML. Children with newly diagnosed ALL were treated according to a protocol which included etoposide 300 mg/m 2 given three times over 8 days during remission induction and once every 2-4 weeks during 120 weeks of continuation therapy. Characteristic 11q23 rearrangements were documented in seven of the eight patients with AML. Etoposide clearance, time that etoposide concentrations exceeded 10 M, etoposide or etoposide catechol area-under-the-plasma-concentration vs time curve (AUC), serum albumin, and average methotrexate concentration did not differ significantly between the two groups; thiopurine methyltransferase (TPMT) activity tended to be lower in the eight children who did vs the 23 matched control children who did not develop AML (P = 0.16). Further regression analyses likewise indicated that lower TPMT activity tended to be associated with shorter onset of secondary AML (P = 0.11); it also tended to be lower among the eight index cases compared to the entire unmatched cohort of 105 identically treated children with ALL (P = 0.10). We observed no statistically significant differences in etoposide disposition and antimetabolite pharmacology between patients who did and did not develop secondary AML.

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Section: Figuresupporting

confidence: 81%

“…The epipodophyllotoxins, etoposide and teniposide, are a class of antineoplastics for which pharmacodynamic relationships have been established: ie plasma concentration of parent drug correlates with both anticancer effect [1][2][3] and acute toxicity (eg myelosuppression).…”

Section: Introductionmentioning

confidence: 99%

Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia

Relling

Yanishevski

Němec³

et al. 1998

Leukemia

176

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“…High etoposide concentrations (>10 µg/ml) were maintained for considerably longer periods in the less effective one day arm than in the superior five day arm (23 versus 11 h, respectively). In a subsequent study in SCLC [14], a five day schedule was compared to an eight day schedule for administration of 500 mg etoposide. In this second study, patients were of poorer performance status than in the initial study and toxicity from etoposide was greater than that seen in the initial trial.…”

Section: Rationale For Chronic Etoposide Therapymentioning

confidence: 99%

The Importance of Drug Scheduling in Cancer Chemotherapy: Etoposide as an Example

Hande

1996

STEM CELLS

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Abstract. Etoposide is a drug whose antineoplastic activity is dependent on the schedule of drug administration. This article reviews the rationale for a prolonged schedule of etoposide administration and the therapeutic results of use of such a schedule in the treatment of cancer. The pharmacology of etoposide is also reviewed, with particular attention paid to the pharmacokinetics of oral etoposide and etoposide plasma concentrations associated with cytotoxicity.

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“…Data from a randomised trial by Clark et al (1994), comparing a schedule of 1 -5 days to a schedule of 1 -8 days, support these findings (Nissen et al, 1976;Lau et al, 1979; Oral etoposide and GM-CSF in advanced ovarian cancer M Baur et al Ogawa et al, 1983;Kimura et al, 1985). Furthermore, two other phase I trials that explored schedules extended to 21 days recommended a dosage of 50 -75 mg m À2 day À1 , which cumulatively corresponds to our total dose of 1000 mg m À2 per cycle (Hainsworth et al, 1989;Noda et al, 1994).…”

Section: Discussionmentioning

confidence: 94%

Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer

et al. 2005

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The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral etoposide given on days 1 -10 followed by rescue with subcutaneous (s.c.) granulocyte-macrophage colony-stimulating factor (GM-CSF) on days 12 -19 as second-line chemotherapy in platinum-pretreated patients (pts) with advanced ovarian carcinoma. Cohorts of three to six pts were treated with doses of oral etoposide from 750 mg m À2 cycle À1 escalated to 1250 mg m À2 cycle À1 over 10 days, every 3 weeks. Subcutanous GM-CSF, 400 mg once daily, days 12 -19, was added if dose-limiting granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70 -100%) and a median time elapsed since the last platinum dose of 10 months (range, 1 -24 months), 30% of whom showed visceral metastases, were treated at four dose levels (DLs) of oral etoposide on days 1 -10 of each cycle as follows: DL 1, 750 mg m À2 cycle À1 , without GM-CSF, three pts; DL 2, 1000 mg m À2 cycle À1 , without GM-CSF, three pts; DL 3, 1000 mg m À2 cycle À1 , with GM-CSF, six pts; and DL 4, 1250 mg m À2 cycle À1 , with GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative sepsis associated with granulocytopenia grade 4. Two more pts developed uncomplicated granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral etoposide 1000 mg m À2 cycle À1 , days 1 -10, followed by s.c. GM-CSF 400 mg, days 12 -19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the therapy with oral etoposide given over 10 days followed by s.c. GM-CSF in platinumpretreated patients with advanced ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.

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A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity.

Cited by 104 publications

References 20 publications

Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia

Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia

The Importance of Drug Scheduling in Cancer Chemotherapy: Etoposide as an Example

Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer

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