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. CONCLUSION: 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.

Clinical trials with 5-fluorouracil, folinic acid and cisplatin in patients with gastrointestinal malignancies.

Combination chemotherapy for advanced gastrointestinal malignancies remains unsatisfactory. Studies show a definite therapeutic advantage for folinic acid/5-fluorouracil (5-FU) regimen compared with single agent 5-FU given intravenously in the management of advanced colorectal cancer. Data on survival benefits vary. A definitive conclusion regarding this question must outweigh the maturation of the present studies and possibly generate further extensive investigations. The currently available data are insufficient from which to draw any conclusion on the effect of the attempt to modulate 5-FU activity further by the addition of cisplatin to the combination. Nevertheless, the combination appears to elicit some therapeutic advantage in patients with pancreatic carcinoma and rectal carcinoma. The paucity of data in gastric carcinoma is disappointing in light of sensitivity to both cisplatin and 5-FU.

Hemolytic uremic syndrome in a patient with small cell lung cancer.

Hemolytic uremic syndrome is a rare entity in patients with carcinoma and presents with a triad of renal insufficiency, microangiopathic hemolytic anemia, and thrombocytopenia. We report this syndrome for the first time in a patient with small cell lung carcinoma. Spontaneous platelet aggregation of washed normal platelets was demonstrated using patient plasma. Circulating immune complex levels were not elevated. The entity completely resolved after treatment with plasma, vincristine, aspirin, and dipyridamole.