A prospective, randomized study of low molecular weight as supplemental therapy in metastatic colorectal cancer patients treated with FOLFIRI regimen and target agents.

Abstract

746 Background: Fucoidan is recently studied for its anti-cancer and anti-inflammatory effects. It also has been used as food supplements in Asia for many years. This study is the first prospective, randomized trial to compare the clinical outcomes and adverse events in metastatic colorectal cancer (mCRC) patients, who are treated with FOLFIRI regimen and target agents as the first line setting with or without low molecular weight Fucoidan (LMF). Additionally, the study also aimed to evaluate the inhibitory effect of LMF in EGFR-KRAS-BRAF-ERK signaling pathway. Methods: A total of 54 patients with mCRC were randomly divided into a study group (28 cases, 4g BID oral low molecular weight Fucoidan powder) and a control group (26 cases, 4g BID oral placebo powder). The supplements were given for 6 months during the therapeutic period. The primary endpoint was the disease-control rate (DCR), and the secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and adverse effects between the two groups. MTT cell viability assay and western blotting analysis were used to evaluate synergic effect of LMF plus 5-FU or Cetuximab on Caco-2, SW620 and HCT-15. Results: 54 mCRC patients were enrolled, including 28 patients in the study group and 26 patients in the control group. The DCR was 92.8% vs. 69.2% in study and control group respectively ( P = 0.026) in median follow up time of 11.5 months. The PFS was 15.93 ± 1.20 vs. 10.80 ± 1.06 months ( P = 0.075), ORR was 60.7% vs. 46.2% ( P = 0.284) and OS was 18.04 ± 0.91 vs. 12.96 ± 0.83 months ( P= 0.092). There were no statistical differences in adverse effects between two groups. In vitrostudy, LMF plus 5-FU or Cetuximab showed synergic cytotoxic effect (maximal 24% increase) through the inhibition of the expression of p-EGFR, p-ERK and p-Akt. Conclusions: The preliminary results show that LMF as supplemental therapy in mCRC patients may improve DCR. In vitro, Fucoidan showed the synergic cytotoxic effect with 5-FU or Cetuximab. The possible mechanism may involve the inhibition effect of Fucoidan in phosphorylation of EGFR-KRAS-BRAF-ERK signaling pathway.