Activity of continuous-infusion 5-fluorouracil in patients with advanced colorectal cancer clinically resistant to bolus 5-fluorouracil

Abstract

We have recently demonstrated that continuous-infusion (CI) 5-fluorouracil (FU) eradicates human colon carcinoma cells made resistant to bolus FU in vitro. In addition, in the same experimental system, the mechanisms of resistance to pulse and CI FU were found to be different. These observations led us to test the clinical activity of a standard regimen of CI FU (300 mg/m2 per day) in a cohort of 15 patients with advanced measurable colorectal cancer who were in progression after having failed to respond to bolus treatment with FU alone (3 patients) or FU combined with high-dose 6-S-leucovorin (LV) (12 patients). The median age of the patients was 68 years, and their median Eastern Cooperative Oncology Group performance status (ECOG PS) was 1. No myelotoxicity was observed. Mild diarrhea, mucositis, and vomiting occurred in 32%, 26%, and 19% of the patients, respectively, with no WHO grade 3 or 4 episodes being noted. In all, 6 of 15 patients complained of hand-foot syndrome, which was severe in 2 instances, lasting approximately 1 week. Overall, 1 partial response and 6 instances of disease stabilization, including 3 minor responses, were obtained both in patients who had been pretreated with pulse FU alone and in patients who had failed first-line treatment with FU + LV. Finally, 8 patients failed CI FU. In conclusion, these results, obtained in patients who were clearly progressing after having failed first-line treatment, support our experimental finding that resistance to bolus FU may be overcome by CI FU and extend this possibility to patients who are resistant to bolus treatment with FU + LV.

A Randomized, Phase II Trial of Standard Triweekly Compared with Dose-Dense Biweekly Capecitabine Plus Oxaliplatin Plus Bevacizumab as First-Line Treatment for Metastatic Colorectal Cancer: XELOX-A-DVS (Dense Versus Standard)

“…Low-dose, continuous infusion 5-FU produces a higher response rate than with other 5-FU regimens [3][4][5][6], but issues associated with continuous infusion remain.…”

Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin

“…The median time to progression for patients receiving second-line therapy is approximately 3 months and the median survival of these patients is 6-8 months. [12][13][14][15] A randomized phase III trial compared continuous infusion 5-FU to Irinotecan among patients who had failed prior treatment with a 5-FU regimen. 10 Only one partial response (PR) (0.7%) was observed among 134 patients treated with continuous infusion 5-FU and 6 (4.5%) PRs were observed in the irinotecan arm.…”

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

“…17 The objective response rate for patients in this study was 8% and the median survival was 11 months, exceeding the expected response rate of 2-5% and survival of 4-6 months for patients with refractory colorectal cancer. [18][19][20][21][22] Although the objective response rate was encouraging, standard radiographic response criteria may not have captured important clinical responses with this biologically active agent. 12,17,23 Forty-six percent of the patients in the phase II study demonstrated transient enlargement of the tumor masses 3 weeks after administration of Onyx-015 followed by regression of the tumors starting 2-3 months after initiation of therapy.…”