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.
OBJECTIVE
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.


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/m(2) intravenously by 24-hour infusion on days 1, 8, 15, 22, 29, and 36. Parenteral hydroxyurea (HU) was administered at 4.3 g/m(2) as a 24-hour infusion concurrently with 5FU. Interferon alfa-2a (IFN-alpha2a) 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 > or = 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 > or = 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.


CONCLUSIONS
Combination therapy with high-dose, weekly infusional HU and 5FU with IFN-alpha2a modulation was well-tolerated with activity in gastric cancer. Patients > or = 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.
Wadler
S
S
Departments of Oncology, Surgery, and Radiology, Montefiore Medical Center, and the Albert Einstein Cancer Center, Bronx, NY 10467, USA. wadler@jimmy.harvard.edu
Damle
S
S
Haynes
H
H
Kaleya
R
R
Schechner
R
R
Berkenblit
R
R
Ladner
R D
RD
Murgo
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy*; D003856:Deoxyuracil Nucleotides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011994:Recombinant Proteins; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013942:Thymine Nucleotides / Q000378:metabolism; D016896:Treatment Outcome
D003856:Deoxyuracil Nucleotides; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013942:Thymine Nucleotides; C027078:deoxyuridine triphosphate; C024157:thymidine 5'-triphosphate; D005472:Fluorouracil; D006918:Hydroxyurea