Impact of pre-angiogenic factors on the treatment effect of bevacizumab in patients with metastatic colorectal cancer.

Endothelin-1 (ET-1) and asymmetric dimethylarginine (ADMA) play a major role in tumor growth and metastasis. Our aim was to determine whether there is any association between these endothelial parameters and tumor markers with the clinical outcome of bevacizumab-treated metastatic colorectal cancer (mCRC) patients in terms of response and survival. Pretreatment serum levels of ET-1, ADMA, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 were measured in 36 chemotherapy-naive mCRC patients treated with first-line bevacizumab-based therapy. Additionally, after first cycle of treatment, serum levels of these parameters were reanalyzed. Lower baseline serum ET-1 and ADMA levels were observed in patients responding to bevacizumab-based treatment (respectively, p = 0.037, p = 0.034). Median progression-free survival (PFS) (11 vs. 6 months, p = 0.012) and overall survival (OS) (28 vs 9 months; p = 0.007) were significantly shorter in patients with high pretreatment ET-1 levels. There was a significant decrease in ET-1 and CEA levels after first treatment (p = 0.020, p = 0.012), while ADMA and CA 19-9 levels were not significantly changed. Patients with decreased posttreatment ET-1 levels were shown to have inferior PFS (6 vs 11 months, p = 0.022), but no statistically significant difference was shown with respect to OS (p = 0.141). The effect of bevacizumab on endothelin axis including the biologic basis of decreasing ET-1 levels due to bevacizumab treatment and its association with inferior outcome has to be clarified in prospective trials.