Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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. Clin Cancer Res; 16(11); 3019-27. ©2010 AACR.For the last 40 years, 5-fluorouracil (5-FU) has been the most active chemotherapeutic agent for colorectal cancer (CRC). The reported response rate to single-agent 5-FU ranges from 10% to 30% (1). Yet, the median survival of patients with advanced CRC has remained ∼12 months (2). In the past decade, new agents, oxaliplatin, irinotecan (CPT-11), bevacizumab, panitumumab, and cetuximab, have been introduced into the clinical practice. Irinotecan as a single agent has shown a 10% response rate in patients with CRC (1, 3). However, the combination of Irinotecan, Fluorouracil, and leucovorin increased the response rate to ∼40% and the median survival to 14.8 months (4). FOLFIRI has shown an increase in median survival to ∼20 months. Similarly, oxaliplatin as a FOL-FOX regimen resulted in an increase in median survival to 19.5 months (5). Thus, it is only when these agents are combined with 5-FU that significant improvements in response rates and median survival are seen. In the past 2 years, no new agents have been approved in the treatment of CRC. Therefore, it seems likely that the development of 5-FU resistance in CRC cells will have substantial and adverse effects on these promising combination regimens. A major mechanism of 5-FU resistance in CRC is overexpression of the dTMP-synthesizing enzyme thymidylate synthase (TS). The...

The BPL algorithm improves the image quality and lesion contrast and appears to be particularly appropriate for patients with a high BMI as it improves the SNR. However, it will be important for patient follow-up or multicenter studies to use the same algorithm and preferably BPL.