This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wadler, S. Articles by Murgo, A. Search for Related Content PubMed PubMed Citation Articles by Wadler, S. Articles by Murgo, A. Social Bookmarking                            What's 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

From the Departments of Oncology, Surgery, and Radiology, Montefiore Medical Center, and the Albert Einstein Cancer Center, Bronx, NY; Department of Molecular Biology, University of Medicine and Dentistry, New Jersey, Osteopathic School of Medicine, Stratford, NJ; and the Investigational Drug Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Address reprint requests to Scott Wadler, Department of Oncology, Hofheimer One, Montefiore Medical Center, 111 East 210th St, Bronx, NY 10467; email wadler{at}jimmy.harvard.edu

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-2a) 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 peripheral-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-2a 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. Wadler, D. Makower, C. Clairmont, P. Lambert, K. Fehn, and M. Sznol Phase I and Pharmacokinetic Study of the Ribonucleotide Reductase Inhibitor, 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone, Administered by 96-Hour Intravenous Continuous Infusion J. Clin. Oncol., May 1, 2004; 22(9): 1553 - 1563. [Abstract] [Full Text] [PDF]

				K.-D. Lee, T.-W. Liu, C.-W. Wu, C.-M. Tiu, J. M. Liu, T.-R. Chung, J.-Y. Chang, J. Whang-Peng, and L.-T. Chen Non-surgical treatment for afferent loop syndrome in recurrent gastric cancer complicated by peritoneal carcinomatosis: percutaneous transhepatic duodenal drainage followed by 24-hour infusion of high-dose fluorouracil and leucovorin Ann. Onc., July 1, 2002; 13(7): 1151 - 1155. [Abstract] [Full Text] [PDF]