Preclinical and clinical evaluation of 5-fluorouracil biochemical modulation with folinic acid and hydroxyurea for patients with colorectal carcinoma.
BACKGROUND
Approximately 140,000 new cases of colorectal carcinoma will be diagnosed in 1995 in the United States, and more than one-third of these patients will die from progressive disease. Despite the modest improvement in response rate with chemotherapy, little improvement in patient survival has been noted. Consequently, the evaluation of new agents, modalities, and combinations is needed.


METHODS
Two cell lines, HCT 116 and COLO 320 HSR, were treated with various concentrations of 5-fluorouracil (5-FU), folinic acid (FA), and hydroxyurea (HU). Subsequently, 41 patients with advanced, measurable metastatic colorectal carcinoma were enrolled in the study. Patients were treated with oral doses of HU (500 mg) every 8 hours on Days 1 and 2, 5-FU (400-500 mg/m2) intravenously Day 2 and FA (100 mg/m2) intravenously on Day 2 of every week for 6 consecutive weeks, followed by a 2-week rest period. All patients were evaluable for toxicity, and 40 were evaluable for response.


RESULTS
In both cell lines, the combination of 5-FU/FA/HU consistently produced the best cytotoxic effect. Clinically, the maximum tolerated dose of 5-FU was established at a level of 500 mg/m2 (450 mg/m2 for patients older than 70 years of age). Ten patients experienced Grade 3 or 4 toxicity, consisting mainly of diarrhea. Eleven of 40 evaluable patients responded (three complete responses, eight partial responses), with a median survival of 12+ months and time to progression of 8.5+ months.


CONCLUSIONS
The biochemical modulation of 5-FU with FA and HU were significantly effective in treating patients with metastatic colorectal carcinoma. Overall, this regimen was well tolerated with only moderate toxicity. Further studies incorporating intravenous HU as well as a randomized Phase III study of 5-FU/FA/HU versus 5-FU/FA are recommended.
Matei
D
D
Division of Medical Oncology, SUNY at Stony Brook, USA.
Hagag
N
N
Madajewicz
S
S
Chowhan
N
N
Hentschel
P
P
Avvento
L
L
Burns
P
P
Fiore
J
J
Lipera
W
W
Zarrabi
H
H
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D002955:Leucovorin / Q000627:therapeutic use*; D018579:Patient Selection; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D007155:Immunologic Factors; D002955:Leucovorin; D005472:Fluorouracil; D006918:Hydroxyurea