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. Oshaughnessy et al., 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, Blood, 86(8), 1995, pp. 2913-2921
Cumulative thrombocytopenia is a dose-limiting toxicity of dose-intens
ive chemotherapy for advanced breast cancer. In this phase I study, we
have studied the hematologic toxicity associated with sequential inte
rleukin-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 eac
h cytokine administered alone. Ninety-three patients with advanced bre
ast cancer were treated with five cycles of FLAC chemotherapy and eith
er IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered b
y schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedul
e B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent admin
istration of IL-3 and GMCSF for 15 days. Cohorts of patients were trea
ted with one of four dose levels of IL-3 (1, 2.5, 5, and 10 mu g/kg) a
dministered subcutaneously for each schedule of cytokine administratio
n. The GM-CSF dose in all schedules was 5 mu g/kg/day. Sequential IL-3
and GM-CSF (schedule B) was associated with higher platelet nadirs, s
horter durations of platelet counts less than 50,000/mu L, and the nee
d for fewer platelet transfusions over five cycles of FLAC chemotherap
y compared with concurrent cytokines, sequential IL-3 and GM-CSF sched
ule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated wit
h unexpected platelet toxicity. The duration of granulocytopenia after
FLAC chemotherapy was significantly worse with IL-3 alone compared wi
th each of the GM-CSF-containing cytokine regimens. Although no cycle
1 maximum tolerated dose for IL-3 was defined in this study, 5 mu g/kg
was well tolerated over multiple cycles of therapy and is recommended
for future studies. The data from this phase I study suggest that seq
uential IL-3 and GMCSF with IL-3 administered for 9 days before beginn
ing GM-CSF may be superior to shorter durations of IL-3 administered s
equentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either
colony-stimulating factor alone in ameliorating the cumulative hematol
ogic toxicity associated with multiple cycles of FLAC chemotherapy. Ad
ditional studies of sequential IL-3 and GM-CSF are warranted. This is
a US government work. There are no restrictions on its use.