A Phase I Study of 5-Fluorouracil/Leucovorin and Arsenic Trioxide for Patients with Refractory/Relapsed Colorectal Carcinoma

• Published in: Clinical cancer research Vol. 16; no. 11; pp. 3019 - 3027
• Main Authors: ARDALAN, Bach, SUBBARAYAN, Pochi R, LIMA, Mayra, GANJEI-AZAR, Parvin, RAMOS, Yipsel, GONZALEZ, Michael, FERNANDEZ, Anthony, MEZENTSEV, Dmitry, REIS, Isildinha, DUNCAN, Robert, PODOLSKY, Lisa, LEE, Kelvin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-06-2010
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Arsenicals - administration & dosage; Arsenicals - adverse effects; Biological and medical sciences; Colorectal Neoplasms - drug therapy; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil - administration & dosage; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Leucovorin - administration & dosage; Male; Medical sciences; Middle Aged; Oxides - administration & dosage; Oxides - adverse effects; Pharmacology. Drug treatments; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Thymidylate Synthase - metabolism; Tumors; Antineoplastic agent; Relapse; Rectal disease; Colorectal carcinoma; Colorectal cancer; Calcium folinate; Intestinal disease; Fluorouracil; Human; Treatment resistance; Enzyme; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; Patient; Arsenic trioxide; Malignant tumor; Thymidylate synthase; Colonic disease; Treatment; Antimetabolic; Methyltransferases; Phase I trial; Pyrimidine derivatives; Digestive diseases; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-2590

This Phase I study was designed to determine a safe combination dose of 5-fluorouracil (5-FU) and arsenic trioxide (ATO) to treat 5-FU-resistant relapsed/refractory colorectal cancer patients. We studied the effect of ATO in the downregulation of thymidylate synthase (TS) in peripheral blood mononuclear cells and in tumor biopsies.
ATO was administered for 5 consecutive days during the first week and twice during weeks 2 to 3 and once on week 4. 5-FU/leucovorin (LV) was administered on days 8, 15, and 22. A modified accelerated titration design was used. 5-FU was dose escalated first followed by a planned dose increase for ATO.
No dose-limiting toxicities were seen in seven patients who received 0.15 mg/kg ATO; grade 3 toxicities were as follows: neutropenia 1, diarrhea 1, and bowel obstruction 1. In patients receiving 0.20 mg/kg ATO, grade 3 toxicities were QTc prolongation 1, fatigue 4, alkaline phosphatase elevation 2, diarrhea 2, and peripheral edema 1. TS gene expression in peripheral blood mononuclear cell decreased in all patients. Eight tumors were biopsied, four showed TS downregulation, three showed upregulations, and one did not change. Estimated median progression-free survival and overall survival were 3.1 and 13.9 months, respectively. In patients who showed TS increase or no change versus TS reduction, estimated median progression-free survival was 2.6 versus 7.9 months (P = 0.188) and overall survival was 8.6 versus 11.7 months (P = 0.44), respectively.
Thus, we determined 0.20 mg/kg ATO, 2,600 mg/m(2) 5-FU, and 500 mg/m(2) leucovorin (LV) to be the recommended phase II dose.