Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors

Andreas Kaubisch, Ron Kaleya, Hilda Haynes-Lewis, Alla Rozenblit, Scott Wadler

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Purpose: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. Methods: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m2 by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m2 CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 μg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. Results: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. Conclusions: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.

Original languageEnglish (US)
Pages (from-to)337-340
Number of pages4
JournalCancer Chemotherapy and Pharmacology
Volume53
Issue number4
DOIs
StatePublished - Apr 2004

Fingerprint

Phase II Clinical Trials
Hydroxyurea
Neuroendocrine Tumors
Ribonucleotide Reductases
Fluorouracil
Interferons
Tumors
Stomach
Thymidylate Synthase
Biological Factors
Therapeutics
Pancreatic Neoplasms
Intravenous Infusions
Refractory materials
Stomach Neoplasms
Toxicity
Nucleotides
Fatigue of materials
Agranulocytosis
Filgrastim

Keywords

  • Fluorouracil
  • Gastric cancer
  • Hydroxyurea
  • Pancreatic cancer
  • Ribonucleotide reductase
  • Thymidylate synthase

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

@article{ff1a605053b74e1791f3fea42f47df5e,
title = "Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors",
abstract = "Purpose: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. Methods: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m2 by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m2 CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 μg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. Results: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. Conclusions: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.",
keywords = "Fluorouracil, Gastric cancer, Hydroxyurea, Pancreatic cancer, Ribonucleotide reductase, Thymidylate synthase",
author = "Andreas Kaubisch and Ron Kaleya and Hilda Haynes-Lewis and Alla Rozenblit and Scott Wadler",
year = "2004",
month = "4",
doi = "10.1007/s00280-003-0727-4",
language = "English (US)",
volume = "53",
pages = "337--340",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Phase II clinical trial of parenteral hydroxyurea in combination with fluorouracil, interferon and filgrastim in the treatment of advanced pancreatic, gastric and neuroendocrine tumors

AU - Kaubisch, Andreas

AU - Kaleya, Ron

AU - Haynes-Lewis, Hilda

AU - Rozenblit, Alla

AU - Wadler, Scott

PY - 2004/4

Y1 - 2004/4

N2 - Purpose: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. Methods: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m2 by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m2 CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 μg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. Results: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. Conclusions: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.

AB - Purpose: Combined inhibition of ribonucleotide reductase (RR) and thymidylate synthase (TS), the enzymes responsible for a balanced supply of nucleotides for DNA synthesis, has been shown to induce synergistic antiproliferative effects in vitro. In the clinic, prolonged infusion of the RR inhibitor, hydroxyurea (HU), may be more effective than bolus or oral administration of drug. The purpose of the current study was to determine whether dose intensification of parenteral hydroxyurea in combination with fluorouracil could enhance the response rates of the combination against refractory upper gastrointestinal malignancies. Methods: A clinical trial of parenteral, weekly, high-dose HU in combination with weekly, high-dose infusional fluorouracil (5FU) was initiated in patients with advanced pancreatic and gastric cancer. Patients received 5FU 1.3 g/m2 by continuous intravenous infusion (CIVI) daily over 48 h weekly in combination with HU 4.3 g/m2 CIVI per day over 48 h weekly. Patients also received the biologic agent interferon alfa-2a 9 MU subcutaneously (s.c.) three times per week and filgrastim 480 μg s.c. on days 3 (starting after midday), 4, 5, and 6 each week. Each cycle required treatment on days 1 and 8 every 22 days. Results: Enrolled in the study were 32 patients, of whom 30 were evaluable. The median age was 56 years. Primary sites included pancreas (18), gastric (13) and islet cell (1). Despite filgrastim, the major toxicities were hematologic with 15 of 30 patients developing grade 3/4 granulocytopenia. Of the 30 patients, 4 developed grade 3/4 diarrhea. Interferon-mediated fatigue was mild. Of 12 evaluable patients with gastric cancer, 1 had a partial response, and there were no responders among patients with pancreatic cancer. Conclusions: Combined inhibition of RR and TS using this high-dose, weekly, 48-h infusional regimen is not an improvement over single-agent therapy in these tumor types.

KW - Fluorouracil

KW - Gastric cancer

KW - Hydroxyurea

KW - Pancreatic cancer

KW - Ribonucleotide reductase

KW - Thymidylate synthase

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U2 - 10.1007/s00280-003-0727-4

DO - 10.1007/s00280-003-0727-4

M3 - Article

C2 - 14704829

AN - SCOPUS:1642290659

VL - 53

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JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

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