Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract

Scott Wadler, Snehal Damle, Hilda Haynes-Lewis, Ron Kaleya, Richard Schechner, Robert G. Berkenblit, Robert D. Ladner, Anthony Murgo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. Patients and Methods: A single- institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m2 intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m2 as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-α2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripherol- blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. Results: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients ≥ 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients ≥ 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. Conclusion: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-α2a modulation was well-tolerated with activity in gastric cancer. Patients ≥ 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.

Original languageEnglish (US)
Pages (from-to)1771-1778
Number of pages8
JournalJournal of Clinical Oncology
Volume17
Issue number6
StatePublished - Jun 1999
Externally publishedYes

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Hydroxyurea
Fluorouracil
Gastrointestinal Tract
Neoplasms
Stomach
Carcinoma
interferon alfa-2a
gemcitabine
Therapeutics
Blood Cells
Mucositis
Agranulocytosis
Leukopenia
DNA-Directed DNA Polymerase
Adjuvant Chemotherapy
Thrombocytopenia
Pharmaceutical Preparations
Stomach Neoplasms
Vomiting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract. / Wadler, Scott; Damle, Snehal; Haynes-Lewis, Hilda; Kaleya, Ron; Schechner, Richard; Berkenblit, Robert G.; Ladner, Robert D.; Murgo, Anthony.

In: Journal of Clinical Oncology, Vol. 17, No. 6, 06.1999, p. 1771-1778.

Research output: Contribution to journalArticle

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title = "Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract",
abstract = "Purpose: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. Patients and Methods: A single- institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m2 intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m2 as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-α2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripherol- blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. Results: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22{\%} of patients ≥ 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49{\%}), granulocytopenia (55{\%}), and thrombocytopenia (22{\%}). Severe diarrhea occurred in 12{\%}, mucositis in 0{\%}, and vomiting in 10{\%} of patients. Patients ≥ 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7{\%}) complete responders and 11 (37{\%}) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. Conclusion: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-α2a modulation was well-tolerated with activity in gastric cancer. Patients ≥ 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.",
author = "Scott Wadler and Snehal Damle and Hilda Haynes-Lewis and Ron Kaleya and Richard Schechner and Berkenblit, {Robert G.} and Ladner, {Robert D.} and Anthony Murgo",
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T1 - Phase II/pharmacodynamic trial of dose-intensive, weekly parenteral hydroxyurea and fluorouracil administered with interferon alfa-2a in patients with refractory malignancies of the gastrointestinal tract

AU - Wadler, Scott

AU - Damle, Snehal

AU - Haynes-Lewis, Hilda

AU - Kaleya, Ron

AU - Schechner, Richard

AU - Berkenblit, Robert G.

AU - Ladner, Robert D.

AU - Murgo, Anthony

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N2 - Purpose: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. Patients and Methods: A single- institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m2 intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m2 as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-α2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripherol- blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. Results: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients ≥ 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients ≥ 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. Conclusion: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-α2a modulation was well-tolerated with activity in gastric cancer. Patients ≥ 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.

AB - Purpose: Combined depletion of pyrimidine and purine DNA precursors has resulted in therapeutic synergism in vitro. The aims of the current study were to test this strategy in patients with refractory tumors and to assess its effects on selected nucleotide pools. Patients and Methods: A single- institution phase II trial was initiated in patients with advanced carcinomas of the stomach and pancreas. Patients had measurable disease and had no prior chemotherapy except adjuvant fluorouracil (5FU) or gemcitabine. 5FU was administered by CADD + pump at 2.6 g/m2 intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m2 as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-α2a) was administered at 9 million units subcutaneously on days 1, 3, and 5 each week. No drug was administered in weeks 7 and 8. Pharmacodynamic studies were performed to assess drug effects on levels of deoxyuridine triphosphate (dUTP) and thymidine triphosphate (TTP) pools in peripherol- blood mononuclear cells (PBMCs) before and 6 hours after treatment using a highly sensitive DNA polymerase assay. Results: There were 53 patients enrolled onto the study (gastric carcinoma, 31; pancreatic carcinoma, 22). The median age was 61 years, with 22% of patients ≥ 70 years old. The predominant grade 3 to 4 toxicities were leukopenia (49%), granulocytopenia (55%), and thrombocytopenia (22%). Severe diarrhea occurred in 12%, mucositis in 0%, and vomiting in 10% of patients. Patients ≥ 70 years had no greater incidence of toxicities. Among the 30 assessable patients with gastric carcinoma, there were two (7%) complete responders and 11 (37%) partial responders (median duration, 7 months). Among the 21 assessable patients with pancreatic carcinoma, there was one responder. Median survival among all patients with gastric carcinoma was 10 months and 13 months for patients with pancreatic carcinoma. Twenty-three patients had samples studied for levels of dUTP and TTP. There was no change in the levels of TTP before and after treatment. Furthermore, dUTP was detected in only five of 28 samples after treatment with no increase in the dUTP/TTP ratio. Conclusion: Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-α2a modulation was well-tolerated with activity in gastric cancer. Patients ≥ 70 years tolerated therapy as well as younger patients. This was the first study to correlate levels of TTP and dUTP after treatment with clinical outcome. In PBMCs used as a surrogate tissue, HU abrogated the 5FU-induced increase in dUTP levels without reversing the overall efficacy of the regimen.

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