A phase I study of 5-fluorouracil, leucovorin and levamisole

• Published in: Cancer chemotherapy and pharmacology Vol. 39; no. 4; pp. 300 - 306
• Main Authors: CLEARY, J. F, ARZOOMANIAN, R, ALBERTI, D, FEIERABEND, C, STORER, B, WITT, P, CARBONE, P, WILDING, G
• Format: Journal Article
• Language: English
• Published: Berlin Springer 1997
• Subjects: Adjuvants, Immunologic - adverse effects; Adjuvants, Immunologic - therapeutic use; Adult; Aged; Antidotes - adverse effects; Antidotes - therapeutic use; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Colonic Neoplasms - drug therapy; Diarrhea - chemically induced; Female; Fluorouracil - adverse effects; Fluorouracil - therapeutic use; Humans; Leucovorin - adverse effects; Leucovorin - therapeutic use; Levamisole - adverse effects; Levamisole - therapeutic use; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Stomatitis - chemically induced; Antineoplastic agent; Drug combination; Toxicity; Fluoropyrimidine derivatives; Levamisole; Calcium folinate; Malignant tumor; Immunomodulator; Chemotherapy; Treatment; Phase I trial; Digestive diseases; Intestinal disease; Advanced stage; Colon; Fluorouracil
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800050576

The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. A group of 38 patients with incurable metastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1-5). Levamisole was administered orally (days 1-3 and 15-17) at doses from 30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies.