A phase I study of sequential versus concurrent interleukin-3 and
granulocyte-macrophage colony-stimulating factor in advanced breast cancer
patients treated with FLAC (5-fluorouracil, leucovorin, doxorubicin,
cyclophosphamide) chemotherapy
JA O'Shaughnessy, DJ Venzon, M Gossard, MH Noone, A Denicoff, A Tolcher, D Danforth, J Jacobson, P Keegan and L Miller
Medicine Branch, National Institutes of Health, Bethesda, MD, USA.
Cumulative thrombocytopenia is a dose-limiting toxicity of dose- intensive
chemotherapy for advanced breast cancer. In this phase I study, we have
studied the hematologic toxicity associated with sequential interleukin-3
(IL-3) and granulocyte-macrophage colony- stimulating factor (GM-CSF;
molgramostim) administration after multiple cycles of FLAC (5-fluorouracil,
leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that
after concurrent cytokine administration or to each cytokine administered
alone. Ninety- three patients with advanced breast cancer were treated with
five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone,
sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3
followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6
days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15
days. Cohorts of patients were treated with one of four dose levels of IL-3
(1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each
schedule of cytokine administration. The GM-CSF dose in all schedules was 5
micrograms/kg/day. Sequential IL-3 and GM- CSF (schedule B) was associated
with higher platelet nadirs, shorter durations of platelet counts less than
50,000/microL, and the need for fewer platelet transfusions over five
cycles of FLAC chemotherapy compared with concurrent cytokines, sequential
IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF
was associated with unexpected platelet toxicity. The duration of
granulocytopenia after FLAC chemotherapy was significantly worse with IL-3
alone compared with each of the GM-CSF-containing cytokine regimens.
Although no cycle 1 maximum tolerated dose for IL-3 was defined in this
study, 5 micrograms/kg was well tolerated over multiple cycles of therapy
and is recommended for future studies. The data from this phase I study
suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days
before beginning GM-CSF may be superior to shorter durations of IL- 3
administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and
to either colony-stimulating factor alone in ameliorating the cumulative
hematologic toxicity associated with multiple cycles of FLAC chemotherapy.
Additional studies of sequential IL-3 and GM-CSF are warranted.
Volume 86,
Issue 8,
pp. 2913-2921,
10/15/1995
Copyright © 1995 by The American Society of Hematology
