A pilot study of interferon α-2a, fluorouracil, and leucovorin given with granulocyte-macrophage colony stimulating factor in advanced gastrointestinal adenocarcinoma

Jeremy D. Shapiro, Nancy Harold, Chris Takimoto, J. Michael Hamilton, David Vaughn, Alice Chen, Seth M. Steinberg, David Liewehr, Carmen Allegra, Brian Monahan, Alex Lash, Frank Grollman, Donald Flemming, Katherine Behan, Patrick G. Johnston, Daniel Haller, Mary Quinn, Geraldine Morrison, Jean L Grem

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Abstract

We reported previously that the addition of recombinant Escherichia coli human granulocyte-macrophage colony stimulating factor (GM-CSF) to a 5- fluorouracil (5-FU) and leucovorin (LV) regimen seemed to ameliorate diarrhea and permit increased 5-FU dose intensity (J. L. Greta et al., J. Clin. Oncol., 12: 560-568, 1994). We then tested the effect of GM-CSF given with a more toxic regimen of 5-FU/LV/IFN-α (IFN α-2a). Thirty-one patients with a good performance status and no prior chemotherapy for systemic disease received IFN α-2a (5 MU/m2 s.c., days 1-7), 5-FU (370 mg/m2 i.v., days 2- 6), LV (500 mg/m2 i.v., days 2-6), and GM-CSF (Saccharomyces cerevisiae 250 μg/m2 s.c., days 7-18) every 3 weeks. Toxicities and 5-FU dose intensity were compared with that observed in our prior Phase II trial with 5-FU/LV/IFN α-2a (J. L. Grem et al., J. Clin. Oncol., 11: 1737-1745, 1993). In comparison with the prior Phase 11 study, the WBC and granulocyte nadirs in the present trial were significantly higher. When trends in toxicity grades for all cycles were compared, stratifying for 5-FU dose, the incidence and severity of mucositis, skin rash, WBC toxicity, and granulocyte toxicity were significantly lower in the present trial, whereas nausea/vomiting and fatigue were significantly worse. The delivered 5-FU dose intensity for all cycles of therapy appeared to be significantly higher in the present trial. Six of 28 evaluable patients had a partial response (21.4%), and 13 (46%) had stable disease for ≥12 weeks. Despite treatment-related toxicity, patient quality of life did not worsen during the study. No correlation was observed between thymidylate synthase content in primary tumor specimens and response, time to treatment failure, or survival. The addition of GM-CSF appeared to decrease the severity of leukopenia, granulocytopenia, mucositis, and skin rash when compared with our prior experience with this regimen of 5-FU/LV/IFN α-2a, at the cost of greater nausea/vomiting and fatigue. The potential impact of increased 5-FU dose intensity on clinical response, however, remains to be determined.

Original languageEnglish (US)
Pages (from-to)2399-2408
Number of pages10
JournalClinical Cancer Research
Volume5
Issue number9
StatePublished - Sep 1 1999

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Leucovorin
Granulocyte-Macrophage Colony-Stimulating Factor
Fluorouracil
Interferons
Adenocarcinoma
Mucositis
Exanthema
Granulocytes
Nausea
Vomiting
Fatigue
Thymidylate Synthase
Agranulocytosis
Poisons
Leukopenia
Treatment Failure
Reaction Time
Saccharomyces cerevisiae
Diarrhea
Quality of Life

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A pilot study of interferon α-2a, fluorouracil, and leucovorin given with granulocyte-macrophage colony stimulating factor in advanced gastrointestinal adenocarcinoma. / Shapiro, Jeremy D.; Harold, Nancy; Takimoto, Chris; Hamilton, J. Michael; Vaughn, David; Chen, Alice; Steinberg, Seth M.; Liewehr, David; Allegra, Carmen; Monahan, Brian; Lash, Alex; Grollman, Frank; Flemming, Donald; Behan, Katherine; Johnston, Patrick G.; Haller, Daniel; Quinn, Mary; Morrison, Geraldine; Grem, Jean L.

In: Clinical Cancer Research, Vol. 5, No. 9, 01.09.1999, p. 2399-2408.

Research output: Contribution to journalArticle

Shapiro, JD, Harold, N, Takimoto, C, Hamilton, JM, Vaughn, D, Chen, A, Steinberg, SM, Liewehr, D, Allegra, C, Monahan, B, Lash, A, Grollman, F, Flemming, D, Behan, K, Johnston, PG, Haller, D, Quinn, M, Morrison, G & Grem, JL 1999, 'A pilot study of interferon α-2a, fluorouracil, and leucovorin given with granulocyte-macrophage colony stimulating factor in advanced gastrointestinal adenocarcinoma', Clinical Cancer Research, vol. 5, no. 9, pp. 2399-2408.
Shapiro, Jeremy D. ; Harold, Nancy ; Takimoto, Chris ; Hamilton, J. Michael ; Vaughn, David ; Chen, Alice ; Steinberg, Seth M. ; Liewehr, David ; Allegra, Carmen ; Monahan, Brian ; Lash, Alex ; Grollman, Frank ; Flemming, Donald ; Behan, Katherine ; Johnston, Patrick G. ; Haller, Daniel ; Quinn, Mary ; Morrison, Geraldine ; Grem, Jean L. / A pilot study of interferon α-2a, fluorouracil, and leucovorin given with granulocyte-macrophage colony stimulating factor in advanced gastrointestinal adenocarcinoma. In: Clinical Cancer Research. 1999 ; Vol. 5, No. 9. pp. 2399-2408.
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abstract = "We reported previously that the addition of recombinant Escherichia coli human granulocyte-macrophage colony stimulating factor (GM-CSF) to a 5- fluorouracil (5-FU) and leucovorin (LV) regimen seemed to ameliorate diarrhea and permit increased 5-FU dose intensity (J. L. Greta et al., J. Clin. Oncol., 12: 560-568, 1994). We then tested the effect of GM-CSF given with a more toxic regimen of 5-FU/LV/IFN-α (IFN α-2a). Thirty-one patients with a good performance status and no prior chemotherapy for systemic disease received IFN α-2a (5 MU/m2 s.c., days 1-7), 5-FU (370 mg/m2 i.v., days 2- 6), LV (500 mg/m2 i.v., days 2-6), and GM-CSF (Saccharomyces cerevisiae 250 μg/m2 s.c., days 7-18) every 3 weeks. Toxicities and 5-FU dose intensity were compared with that observed in our prior Phase II trial with 5-FU/LV/IFN α-2a (J. L. Grem et al., J. Clin. Oncol., 11: 1737-1745, 1993). In comparison with the prior Phase 11 study, the WBC and granulocyte nadirs in the present trial were significantly higher. When trends in toxicity grades for all cycles were compared, stratifying for 5-FU dose, the incidence and severity of mucositis, skin rash, WBC toxicity, and granulocyte toxicity were significantly lower in the present trial, whereas nausea/vomiting and fatigue were significantly worse. The delivered 5-FU dose intensity for all cycles of therapy appeared to be significantly higher in the present trial. Six of 28 evaluable patients had a partial response (21.4{\%}), and 13 (46{\%}) had stable disease for ≥12 weeks. Despite treatment-related toxicity, patient quality of life did not worsen during the study. No correlation was observed between thymidylate synthase content in primary tumor specimens and response, time to treatment failure, or survival. The addition of GM-CSF appeared to decrease the severity of leukopenia, granulocytopenia, mucositis, and skin rash when compared with our prior experience with this regimen of 5-FU/LV/IFN α-2a, at the cost of greater nausea/vomiting and fatigue. The potential impact of increased 5-FU dose intensity on clinical response, however, remains to be determined.",
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AU - Vaughn, David

AU - Chen, Alice

AU - Steinberg, Seth M.

AU - Liewehr, David

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AU - Monahan, Brian

AU - Lash, Alex

AU - Grollman, Frank

AU - Flemming, Donald

AU - Behan, Katherine

AU - Johnston, Patrick G.

AU - Haller, Daniel

AU - Quinn, Mary

AU - Morrison, Geraldine

AU - Grem, Jean L

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N2 - We reported previously that the addition of recombinant Escherichia coli human granulocyte-macrophage colony stimulating factor (GM-CSF) to a 5- fluorouracil (5-FU) and leucovorin (LV) regimen seemed to ameliorate diarrhea and permit increased 5-FU dose intensity (J. L. Greta et al., J. Clin. Oncol., 12: 560-568, 1994). We then tested the effect of GM-CSF given with a more toxic regimen of 5-FU/LV/IFN-α (IFN α-2a). Thirty-one patients with a good performance status and no prior chemotherapy for systemic disease received IFN α-2a (5 MU/m2 s.c., days 1-7), 5-FU (370 mg/m2 i.v., days 2- 6), LV (500 mg/m2 i.v., days 2-6), and GM-CSF (Saccharomyces cerevisiae 250 μg/m2 s.c., days 7-18) every 3 weeks. Toxicities and 5-FU dose intensity were compared with that observed in our prior Phase II trial with 5-FU/LV/IFN α-2a (J. L. Grem et al., J. Clin. Oncol., 11: 1737-1745, 1993). In comparison with the prior Phase 11 study, the WBC and granulocyte nadirs in the present trial were significantly higher. When trends in toxicity grades for all cycles were compared, stratifying for 5-FU dose, the incidence and severity of mucositis, skin rash, WBC toxicity, and granulocyte toxicity were significantly lower in the present trial, whereas nausea/vomiting and fatigue were significantly worse. The delivered 5-FU dose intensity for all cycles of therapy appeared to be significantly higher in the present trial. Six of 28 evaluable patients had a partial response (21.4%), and 13 (46%) had stable disease for ≥12 weeks. Despite treatment-related toxicity, patient quality of life did not worsen during the study. No correlation was observed between thymidylate synthase content in primary tumor specimens and response, time to treatment failure, or survival. The addition of GM-CSF appeared to decrease the severity of leukopenia, granulocytopenia, mucositis, and skin rash when compared with our prior experience with this regimen of 5-FU/LV/IFN α-2a, at the cost of greater nausea/vomiting and fatigue. The potential impact of increased 5-FU dose intensity on clinical response, however, remains to be determined.

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