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

J. A. O'Shaughnessy, D. J. Venzon, M. Gossard, M. H. Noone, A. Denicoff, A. Tolcher, D. Danforth, J. Jacobson, P. Keegan, L. Miller, C. Chow, B. Goldspiel, Kenneth H Cowan

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Abstract

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 μg/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 μg/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/μL, 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 μg/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.

Original languageEnglish (US)
Pages (from-to)2913-2921
Number of pages9
JournalBlood
Volume86
Issue number8
StatePublished - Nov 9 1995
Externally publishedYes

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Chemotherapy
Leucovorin
Interleukin-3
Granulocyte-Macrophage Colony-Stimulating Factor
Fluorouracil
Doxorubicin
Cyclophosphamide
Breast Neoplasms
Drug Therapy
Appointments and Schedules
Platelets
Toxicity
Cytokines
Blood Platelets
Colony-Stimulating Factors
Platelet Transfusion
Agranulocytosis
Maximum Tolerated Dose

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

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. / O'Shaughnessy, J. A.; Venzon, D. J.; Gossard, M.; Noone, M. H.; Denicoff, A.; Tolcher, A.; Danforth, D.; Jacobson, J.; Keegan, P.; Miller, L.; Chow, C.; Goldspiel, B.; Cowan, Kenneth H.

In: Blood, Vol. 86, No. 8, 09.11.1995, p. 2913-2921.

Research output: Contribution to journalArticle

O'Shaughnessy, JA, Venzon, DJ, Gossard, M, Noone, MH, Denicoff, A, Tolcher, A, Danforth, D, Jacobson, J, Keegan, P, Miller, L, Chow, C, Goldspiel, B & Cowan, KH 1995, '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, vol. 86, no. 8, pp. 2913-2921.
O'Shaughnessy, J. A. ; Venzon, D. J. ; Gossard, M. ; Noone, M. H. ; Denicoff, A. ; Tolcher, A. ; Danforth, D. ; Jacobson, J. ; Keegan, P. ; Miller, L. ; Chow, C. ; Goldspiel, B. ; Cowan, Kenneth H. / 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. In: Blood. 1995 ; Vol. 86, No. 8. pp. 2913-2921.
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abstract = "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 μg/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 μg/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/μL, 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 μg/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.",
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T1 - 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

AU - O'Shaughnessy, J. A.

AU - Venzon, D. J.

AU - Gossard, M.

AU - Noone, M. H.

AU - Denicoff, A.

AU - Tolcher, A.

AU - Danforth, D.

AU - Jacobson, J.

AU - Keegan, P.

AU - Miller, L.

AU - Chow, C.

AU - Goldspiel, B.

AU - Cowan, Kenneth H

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N2 - 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 μg/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 μg/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/μL, 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 μg/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.

AB - 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 μg/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 μg/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/μL, 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 μg/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.

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